Gene Report

Basic Information

Approved Symbol	TNF
Approved Name	tumor necrosis factor
Previous Symbol	TNFA
Previous Name	tumor necrosis factor (TNF superfamily, member 2)
Symbol Alias	TNFSF2, DIF, TNF-alpha
Name Alias	TNF superfamily, member 2
Location	6p21.3
Position	chr6:31543344-31546113 (+)
External Links	Entrez Gene: 7124 Ensembl: ENSG00000232810 UCSC: uc003nui.3 HGNC ID: 11892
No. of Studies (Positive/Negative)	5(5/0)
Type	Literature-origin; SNP mapped; Protein mapped

Positive relationships between TNF and MDD (count: 4)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
TNF	Bosker, 2010	patients and normal controls	OR T = 1.35, 95% CI 1.13-1.63; P-value = 0.0034	the only gene for which the association with MDD remained si...... the only gene for which the association with MDD remained significant after correction for multiple testing (rs76917; OR T = 1.35, 95% CI 1.13-1.63; P = 0.0034) More...
tumour necrosis factor-alpha	Jun, 2003	patients and normal controls	P-value<0.05	Genotype and allele distributions in patients with MDD (P=0....... Genotype and allele distributions in patients with MDD (P=0.024 and P=0.0125, respectively), were significantly different from those of the controls. In particular, subjects with MDD had an increased frequency of the TNF2 (A) allele. More...
TNF-alpha	Cerri, 2010	patients and normal controls	OR 2.433, CI 1.09-5.43	In subjects affected by MD we found a higher percentage of t...... In subjects affected by MD we found a higher percentage of the GG genotype (84 vs. 68,3%; p = 0.007) and thus of the G allele (92 vs. 81,9%; p = 0.05).The GG genotype was associated with a greater risk of developing the disease (OR 2.433, CI 1.09-5.43). More...
TNF-alpha	Cerri AP, 2009	Patients and nomal controls	p=0.007	Our results evidenced a significantly higher percentage of t...... Our results evidenced a significantly higher percentage of the GG genotype in depressed subjects (84.0% vs. 68.3%; p=0.007) and consequently of the G allele (92.0% vs. 81.9%; p=0.05). The presence of the GG genotype raised the risk of developing MD (odds ratio=OR=2.433, confidence interval=Cl=1.09-5.43). More...

Positive relationships between TNF and other components at different levels (count: 1)

Genetic/epigenetic locus					Protein and other molecule			Cell and molecular pathway			Neural system			Cognition and behavior		Symptoms and signs			Environment

Name in Literature	Level	Approved Name (Name in Literature)	Type	Reference	Research Type	Statistical Result	Relation Description	All
Name in Literature	Related Components
TNF		N200(N2)	neurobiological system	Beste, 2010	normal people		Compared with the TNF GG genotype group, attentional proces...... Compared with the TNF GG genotype group, attentional processes (N1) were enhanced in the combined AA/AG genotype group, while conflict processing functions (N2) and the selection of actions (LRP) were reduced. More...

Positive relationship network of TNF in MK4MDD

Network loading ...

Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between TNF and MDD (count: 0)

Negative relationships between TNF and other components at different levels (count: 0)

TNF related SNPs in MK4MDD (count: 1)

#rs	Location	Annotation	No. of Studies (Positive/Negative)
rs1800629	chr6:31543031(Forward)	downstream_gene_variant; upstream_gene_variant	1(1/0)

TNF related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Tumor necrosis factor	P01375	13(10/3)	Literature-origin

TNF related GO terms (count: 123)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0006954	inflammatory response	biological process	IDA[10748004]
GO:0000165	MAPK cascade	biological process	IMP
GO:0043491	protein kinase B signaling cascade	biological process	IMP
GO:0006915	apoptotic process	biological process	TAS

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0050901	leukocyte tethering or rolling	biological process	IDA[10820279]
GO:0060557	positive regulation of vitamin D biosynthetic process	biological process	IDA[1690216]
GO:0060664	epithelial cell proliferation involved in salivary gland morphogenesis	biological process	IEA
GO:0030198	extracellular matrix organization	biological process	IEA
GO:0030730	sequestering of triglyceride	biological process	IDA[19032770]
GO:0061048	negative regulation of branching involved in lung morphogenesis	biological process	IDA[17350185]
GO:0097190	apoptotic signaling pathway	biological process	IDA[10521396]
GO:0005615	extracellular space	cellular component	IDA[18355445]
GO:0045080	positive regulation of chemokine biosynthetic process	biological process	IDA[10490959]
GO:0050806	positive regulation of synaptic transmission	biological process	IEA
GO:0071803	positive regulation of podosome assembly	biological process	IDA[15220135]
GO:0002925	positive regulation of humoral immune response mediated by circulating immunoglobulin	biological process	IEA
GO:2000343	positive regulation of chemokine (C-X-C motif) ligand 2 production	biological process	IDA
GO:0051044	positive regulation of membrane protein ectodomain proteolysis	biological process	IDA[18373975]
GO:0045944	positive regulation of transcription from RNA polymerase II promoter	biological process	IDA; IGI[16803872]
GO:0043122	regulation of I-kappaB kinase/NF-kappaB cascade	biological process	IDA[10748004]
GO:0070265	necrotic cell death	biological process	IDA[11101870]
GO:0044130	negative regulation of growth of symbiont in host	biological process	IEA
GO:0032729	positive regulation of interferon-gamma production	biological process	IEA
GO:0045071	negative regulation of viral genome replication	biological process	IDA[10490959]
GO:0010940	positive regulation of necrotic cell death	biological process	TAS[16507998]
GO:0045840	positive regulation of mitosis	biological process	IEA
GO:0045599	negative regulation of fat cell differentiation	biological process	NAS[16464856]
GO:0009897	external side of plasma membrane	cellular component	ISS
GO:0034116	positive regulation of heterotypic cell-cell adhesion	biological process	IDA
GO:0000060	protein import into nucleus, translocation	biological process	IDA[16280327]
GO:0048661	positive regulation of smooth muscle cell proliferation	biological process	IDA[16518841]
GO:0000122	negative regulation of transcription from RNA polymerase II promoter	biological process	IDA[15345745]
GO:0005164	tumor necrosis factor receptor binding	molecular function	IDA[14512626]
GO:0009615	response to virus	biological process	IDA[10490959]
GO:0002740	negative regulation of cytokine secretion involved in immune response	biological process	IDA[10443688]
GO:0050995	negative regulation of lipid catabolic process	biological process	IDA[19032770]
GO:0051533	positive regulation of NFAT protein import into nucleus	biological process	IDA[16803872]
GO:0045672	positive regulation of osteoclast differentiation	biological process	IDA[17888176]
GO:0051023	regulation of immunoglobulin secretion	biological process	IEA
GO:0031334	positive regulation of protein complex assembly	biological process	IDA[12813029]
GO:0051384	response to glucocorticoid stimulus	biological process	IDA[10443688]
GO:0051897	positive regulation of protein kinase B signaling cascade	biological process	IEA
GO:0042346	positive regulation of NF-kappaB import into nucleus	biological process	IDA[17922812]
GO:0045668	negative regulation of osteoblast differentiation	biological process	IEA
GO:0045416	positive regulation of interleukin-8 biosynthetic process	biological process	IDA
GO:0043525	positive regulation of neuron apoptotic process	biological process	IEA
GO:0032722	positive regulation of chemokine production	biological process	IDA[10490959]
GO:0006927	transformed cell apoptotic process	biological process	IDA[3883195]
GO:0005887	integral to plasma membrane	cellular component	IDA[18355445]
GO:0050715	positive regulation of cytokine secretion	biological process	IDA[10443688]
GO:0005125	cytokine activity	molecular function	IDA[10748004]
GO:0045994	positive regulation of translational initiation by iron	biological process	IEA
GO:0071677	positive regulation of mononuclear cell migration	biological process	NAS
GO:0045429	positive regulation of nitric oxide biosynthetic process	biological process	IDA[8383325]
GO:0000185	activation of MAPKKK activity	biological process	IDA[15310755]
GO:0045893	positive regulation of transcription, DNA-dependent	biological process	IDA[14512626]
GO:0006919	activation of cysteine-type endopeptidase activity involved in apoptotic process	biological process	IDA[14512626]
GO:0031622	positive regulation of fever generation	biological process	ISS
GO:0045892	negative regulation of transcription, DNA-dependent	biological process	IDA[17350185]
GO:0009651	response to salt stress	biological process	TAS[18355445]
GO:0060559	positive regulation of calcidiol 1-monooxygenase activity	biological process	IDA[1690216]
GO:0031663	lipopolysaccharide-mediated signaling pathway	biological process	IDA
GO:0010693	negative regulation of alkaline phosphatase activity	biological process	IEA
GO:0006917	induction of apoptosis	biological process	IDA[18202225]
GO:0033209	tumor necrosis factor-mediated signaling pathway	biological process	IMP[10748004]
GO:0032755	positive regulation of interleukin-6 production	biological process	IEA
GO:0045121	membrane raft	cellular component	IDA[17010968]
GO:0010629	negative regulation of gene expression	biological process	IDA[15345745]
GO:2000010	positive regulation of protein localization to cell surface	biological process	IDA[19366699]
GO:0009986	cell surface	cellular component	IDA[18355445]
GO:0043406	positive regulation of MAP kinase activity	biological process	IDA[12813029]
GO:0001891	phagocytic cup	cellular component	ISS
GO:0071407	cellular response to organic cyclic compound	biological process	IDA
GO:0006959	humoral immune response	biological process	IEA
GO:0060555	activation of necroptosis by extracellular signals	biological process	IDA[11101870]
GO:0048566	embryonic digestive tract development	biological process	IEP
GO:0002037	negative regulation of L-glutamate transport	biological process	IEA
GO:0005886	plasma membrane	cellular component	TAS
GO:0051222	positive regulation of protein transport	biological process	IDA[15310755]
GO:0070374	positive regulation of ERK1 and ERK2 cascade	biological process	NAS[18606301]
GO:0051092	positive regulation of NF-kappaB transcription factor activity	biological process	IDA
GO:0051091	positive regulation of sequence-specific DNA binding transcription factor activity	biological process	IDA[10748004]
GO:0014823	response to activity	biological process	IEA
GO:0046330	positive regulation of JNK cascade	biological process	IEA
GO:0008285	negative regulation of cell proliferation	biological process	IEA
GO:0046325	negative regulation of glucose import	biological process	IEA
GO:0055037	recycling endosome	cellular component	ISS
GO:0032715	negative regulation of interleukin-6 production	biological process	IDA[10443688]
GO:0030316	osteoclast differentiation	biological process	IEA
GO:0019722	calcium-mediated signaling	biological process	IEA
GO:0043065	positive regulation of apoptotic process	biological process	IDA[16723520]; NAS
GO:0050830	defense response to Gram-positive bacterium	biological process	IEA
GO:0008625	extrinsic apoptotic signaling pathway via death domain receptors	biological process	IDA[18676776]
GO:0051798	positive regulation of hair follicle development	biological process	IEA
GO:0071316	cellular response to nicotine	biological process	IDA[18676776]
GO:0002439	chronic inflammatory response to antigenic stimulus	biological process	IMP[14512626]
GO:0009887	organ morphogenesis	biological process	IEA
GO:0000187	activation of MAPK activity	biological process	IDA[10748004]
GO:0009612	response to mechanical stimulus	biological process	IEA
GO:0050796	regulation of insulin secretion	biological process	IDA[8383325]
GO:0010888	negative regulation of lipid storage	biological process	NAS[16464856]
GO:0043068	positive regulation of programmed cell death	biological process	IDA[16611992]
GO:0043066	negative regulation of apoptotic process	biological process	IDA[10666185]
GO:0097191	extrinsic apoptotic signaling pathway	biological process	IDA[16611992]
GO:0042493	response to drug	biological process	IEA
GO:0033138	positive regulation of peptidyl-serine phosphorylation	biological process	IDA[17389591]
GO:0003009	skeletal muscle contraction	biological process	IEA
GO:0001819	positive regulation of cytokine production	biological process	IDA[17922812]
GO:0044212	transcription regulatory region DNA binding	molecular function	IDA[17350185]
GO:0042802	identical protein binding	molecular function	IDA[14512626]
GO:0032800	receptor biosynthetic process	biological process	IDA[10443688]
GO:0006006	glucose metabolic process	biological process	IEA
GO:0043243	positive regulation of protein complex disassembly	biological process	IDA[12813029]
GO:0071230	cellular response to amino acid stimulus	biological process	IEA
GO:0002876	positive regulation of chronic inflammatory response to antigenic stimulus	biological process	IEA
GO:0001775	cell activation	biological process	IEA
GO:0005515	protein binding	molecular function	IPI
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB cascade	biological process	IDA[15310755]
GO:0007254	JNK cascade	biological process	IEA
GO:0001934	positive regulation of protein phosphorylation	biological process	IDA[10748004]
GO:0002020	protease binding	molecular function	IPI[12777399]
GO:0060693	regulation of branching involved in salivary gland morphogenesis	biological process	IEA
GO:0001666	response to hypoxia	biological process	IEA

TNF related KEGG pathways (count: 23)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04940	type i_diabetes_mellitus	Type I diabetes mellitus	Type I diabetes mellitus is a disease that results from auto...... Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma). Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene. More...
hsa05332	graft versus_host_disease	Graft-versus-host disease	Graft-versus-host disease (GVHD) pathophysiology can be summ...... Graft-versus-host disease (GVHD) pathophysiology can be summerized in a three-step process. During step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage, activation of host tissues and induction of inflammatory cytokines secretion. Increased expression of major histocompatibility complex (MHC) antigens and adhesion molecules leads to enhancement of the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells. Donor T-cell activation in step II is characterized by the predominance of Th1 cells and the secretion of IL-2 and IFN-gamma. These cytokines induce further T-cell expansion, induce cytotoxic T lymphocytes (CTL) and natural killer (NK) cells responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. Also, nitric oxide (NO) is produced by activated macrophages, and it may contribute to the tissue damage seen during step 3. Lipopolysaccharide (LPS), which leaks through the intestinal mucosa that was damaged during step 1, together with IFN-gamma, from step 2, further stimulate macrophages to secrete cytokines and NO. During step 3, the effector phase, activated CTL and NK cells mediate cytotoxicity against target host cells through Fas-Fas ligand interactions and perforin-granzyme B. More...

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa05410	hypertrophic cardiomyopathy_hcm	Hypertrophic cardiomyopathy (HCM)	Hypertrophic cardiomyopathy (HCM) is a primary myocardial di...... Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in 11 genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myofilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction. More...
hsa05330	allograft rejection	Allograft rejection	After transplantation of organ allografts, there are two pat...... After transplantation of organ allografts, there are two pathways of antigen presentation. In the direct pathway, recipient T cells react to intact allogeneic MHC molecules expressed on the surface of donor cells. This pathway would activate host CD4 or CD8 T cells. In contrast, donor MHC molecules (and all other proteins) shed from the graft can be taken up by host APCs and presented to recipient T cells in the context of self-MHC molecules - the indirect pathway. Such presentation activates predominantly CD4 T cells. A direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nontheless, T cells with indirect allospecificity can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis, and are also likely to be important in the development of an alloantibody response to graft. More...
hsa04621	nod like_receptor_signaling_pathway	NOD-like receptor signaling pathway	Specific families of pattern recognition receptors are respo...... Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. These NLRs include NALP1, NALP3 and Ipaf. The inflammasomes are critical for generating mature proinflammatory cytokines in concert with Toll-like receptor signaling pathway. More...
hsa04060	cytokine cytokine_receptor_interaction	Cytokine-cytokine receptor interaction	Cytokines are soluble extracellular proteins or glycoprotein...... Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped. More...
hsa05310	asthma	Asthma	Inhaled allergens encounter antigen presenting cells (APC) t...... Inhaled allergens encounter antigen presenting cells (APC) that line the airway. Upon recognition of the antigen and activation by APC, naive T cells differentiate into TH2 cells, a process that is promoted by interleukin 4 (IL-4). Activated TH2 cells stimulate B cells to produce IgE antibodies in response to IL-4 and IL-13. IgE binds the high affinity IgE receptor at the surface of mast cells, the proliferation and differentiation of which is promoted by IL-9.The crosslinking of mast-cell-bound IgE by allergens leads to the release of biologically active mediators (histamine, leukotrienes) by means of degranulation and, so, to the immediate symptoms of allergy. Activated mast cells and Th2 cells also induce the production of IL-5. IL-5 travels to the bone marrow and regulates the differentiation and egress of eosinophils from the bone marrow into the blood. Moreover activated mast cells and Th2 cells in the lung generate the cytokines interleukin IL-4, IL-13 and tumour necrosis factor (TNF)-alpha. These cytokines stimulate the generation of eotaxin by lung epithelial cells, fibroblasts and smooth muscle cells. Eotaxin then stimulates the selective recruitment of eosinophils from the airway microvessels into the lung tissue. The activation of eosinophils leads to release of toxic granules and oxygen free radicals that lead to tissue damage and promote the development of chronic inflammation. More...
hsa04664	fc epsilon_ri_signaling_pathway	Fc epsilon RI signaling pathway	Fc epsilon RI-mediated signaling pathways in mast cells are ...... Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses. More...
hsa04210	apoptosis	Apoptosis	Apoptosis is a genetically controlled mechanisms of cell dea...... Apoptosis is a genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis. More...
hsa05010	alzheimers disease	Alzheimer's disease	Alzheimer's disease (AD) is a chronic disorder that slowly d...... Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. More...
hsa04620	toll like_receptor_signaling_pathway	Toll-like receptor signaling pathway	Specific families of pattern recognition receptors are respo...... Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK. More...
hsa05014	amyotrophic lateral_sclerosis_als	Amyotrophic lateral sclerosis (ALS)	Amyotrophic lateral sclerosis (ALS) is a progressive, lethal...... Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial amyotrophic lateral sclerosis (FALS) cases, may be toxic because it is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS) via aberrant superoxide chemistry. These changes may then result in abnormal mitochondrial energy metabolism, Ca2+ handling, and release of pro-apoptotic factors. Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess causes neurotoxicity by increasing intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions by various means including by increasing levels of peroxynitrite, which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, disrupting their phosphorylation and affecting axonal transport. Collectively, these mechanisms (or a combination thereof) are predicted to disturb cellular homeostasis (within glial and/or motor neurons), ultimately triggering motor neuron death. More...
hsa04622	rig i_like_receptor_signaling_pathway	RIG-I-like receptor signaling pathway	Specific families of pattern recognition receptors are respo...... Specific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular viral replication is recognized by a family of cytosolic RNA helicases termed RIG-I-like receptors (RLRs). The RLR proteins include RIG-I, MDA5, and LGP2 and are expressed in both immune and nonimmune cells. Upon recognition of viral nucleic acids, RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways that lead to the synthesis of type I interferon and other inflammatory cytokines, which are important for eliminating viruses. More...
hsa04010	mapk signaling_pathway	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a hig...... The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli. More...
hsa04920	adipocytokine signaling_pathway	Adipocytokine signaling pathway	Increased adipocyte volume and number are positively correla...... Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect. Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression. The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation. More...
hsa05140	leishmania infection	Leishmania infection	Leishmania is an intracellular protozoan parasite of macroph...... Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses. More...
hsa04930	type ii_diabetes_mellitus	Type II diabetes mellitus	Insulin resistance is strongly associated with type II diabe...... Insulin resistance is strongly associated with type II diabetes. Diabetogenic factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process. The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction. Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively. More...
hsa04650	natural killer_cell_mediated_cytotoxicity	Natural killer cell mediated cytotoxicity	Natural killer (NK) cells are lymphocytes of the innate immu...... Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death. More...
hsa05414	dilated cardiomyopathy	Dilated cardiomyopathy	Dilated cardiomyopathy (DCM) is a heart muscle disease chara...... Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. Genetically inherited forms of DCM (familial DCM) have been identified in 25-35% of patients presenting with this disease, and the inherited gene defects are an important cause of familial DCM. The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. In cases where an underlying pathology cannot be identified, the patient is diagnosed with an idiopathic DCM. Current hypotheses regarding causes of idiopathic DCM focus on chronic viral myocarditis and/or on autoimmune abnormalities. Viral myocarditis may progress to an autoimmune phase and then to progressive cardiac dilatation. Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with idiopathic DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure. More...
hsa04350	tgf beta_signaling_pathway	TGF-beta signaling pathway	The transforming growth factor-beta (TGF-beta) family member...... The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads ( R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins. More...
hsa04660	t cell_receptor_signaling_pathway	T cell receptor signaling pathway	Activation of T lymphocytes is a key event for an efficient ...... Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells. More...
hsa05322	systemic lupus_erythematosus	Systemic lupus erythematosus	Systemic lupus erythematosus (SLE) is characterized by circu...... Systemic lupus erythematosus (SLE) is characterized by circulating IgG autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components. Immune complexes comprising autoantibody and self-antigen is deposited particulary in the renal glomeruli and mediate a systemic inflammatory response by activating complement or via Fc-gamma-R-mediated neutrophil and macrophage activation. Activation of complement leads to injury both through formation of the membrane attack complex (C5b-9) or by generation of the anaphylatoxin and cell activator C5a. Neutrophils and macrophages cause tissue injury by the release of oxidants and proteases. More...
hsa04640	hematopoietic cell_lineage	Hematopoietic cell lineage	Blood-cell development progresses from a hematopoietic stem ...... Blood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid progenitor (CLP) or a common myeloid progenitor (CMP). A CLP gives rise to the lymphoid lineage of white blood cells or leukocytes-the natural killer (NK) cells and the T and B lymphocytes. A CMP gives rise to the myeloid lineage, which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. Cells undergoing these differentiation process express a stage- and lineage-specific set of surface markers. Therefore cellular stages are identified by the specific expression patterns of these genes. More...

TNF related BioCarta pathways (count: 20)

ID	Name	Brief Description	Full Description
Literature-origin BioCarta pathway
NTHI_PATHWAY	nthi pathway	NFkB activation by Nontypeable Hemophilus influenzae	The role of Hemophilus influenzae in ear infections and chro...... The role of Hemophilus influenzae in ear infections and chronic obstructive pulmonary disease includes the induction of an inflammatory response through activation of the transcription factor NF-kB. In addition to activation of inflammatory cytokine genes like IL-1 and TNF, H. influenzae activates TLR2 expression and genes involved in mucus production. Hemophilus influenzae activates NF-kB by multiple mechanisms, starting with activation of the Toll-like receptor 2 (TLR2) by the p16 protein in the H. influenzae outer membrane. TLR2 plays a key role in innate immune responses and is expressed in high levels in lymphoid cells as well as low levels in epithelial cells. The role of TLR2 was supported by blocking NF-kB activation with a dominant negative TLR2 and increasing it with transfection of a normal TLR2 gene. TLR2 in turn activates TAK1, which activates two divergent signaling pathways. One of these pathways leads to IkB kinase activation, IkB phosphorylation and degradation, releasing the NF-kB heterodimer to translocate into the nucleus and activate transcription of target genes. In the alternate pathway, TAK1 also activates NF-kB through a Map kinase pathway, activating p38 and NF-kB in a nuclear translocation independent manner. Investigation of the mechanisms of H. influenzae signaling involved in NF-kB activation may provide the information needed to develop better treatments for inflammatory conditions caused by this pathogen. Other pathways modulate the role of NF-kB in H. influenzae pathogenesis. Glucocorticoids widely used as anti-inflammatory drugs increase TLR2 activation by H. influenzae through the NIK/I-kB kinase pathway, while they repress the p38 dependent activation of NF-kB. The repression of the p38 pathway by glucocorticoids occurs through activation of the MAP kinase phosphatase-1 (MKP-1) which dephosphorylates and deactivates p38. Another aspect of the inflammatory response to H. influenzae infection is the production of excessive mucus, contributing to the overall symptoms of infection. NF-kB activation of the Muc2 gene contributes to mucus overproduction, in addition to H. influenzae activation of the TGF-beta receptor, activating SMAD transcription factors SMAD3 and SMAD4. Understanding mechanisms that modify H. influenzae signaling will contribute to further understanding the pathogenesis and treatment of ear infections and chronic obstructive pulmonary disease. More...

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
SODD_PATHWAY	sodd pathway	SODD/TNFR1 Signaling Pathway	The tumor necrosis factor (TNF) receptor superfamily contain...... The tumor necrosis factor (TNF) receptor superfamily contains several members with homologous cytoplasmic domains known as death domains (DD). The intracellular DD are important in initiating apoptosis and other signaling pathways following ligand binding by the receptors.1 In the absence of ligand, DD-containing receptors are maintained in an inactive state. TNF RI contains a cytoplasmic DD required for signaling pathways associated with apoptosis and NF-kB activation.2,3 Jiang et al.4 identified a widely expressed 60 kDa protein, named SODD (silencer of death domains), associated with the DD of TNF RI and DR3. Overexpression of SODD suppresses TNF-induced cell death and NF-kB activation demonstrating its role as a negative regulatory protein for these signaling pathways. TNF-induced receptor trimerization aggregates the DD of TNF RI and recruits the adapter protein TRADD.3,5 This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD, TRAF2 and RIP to form an active TNF RI signaling complex (Figure 1A).6-9 In contrast, SODD acts as a silencer of TNF RI signaling and does not interact with TRADD, FADD, or RIP (Figure 1B).4 It is associated with the DD of TNF RI and maintains TNF RI in an inactive, monomeric state. TNF-induced aggregation of TNF RI promotes the disruption of the SODD-TNF RI complex. SODD does not interact with the DD of other TNF receptor superfamily members such as Fas, DR4, DR5, or TNF RII. SODD association with TNF RI may represent a general model for the prevention of spontaneous TNF signaling by other DD-containing receptors. More...
CYTOKINE_PATHWAY	cytokine pathway	Cytokine Network	Several different cell types coordinate their efforts as par...... Several different cell types coordinate their efforts as part of the immune system, including B cells, T cells, macrophages, neutrophils, basophils and eosinophils. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted factors called cytokines, including interleukins, TNF, and the interferons. Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types. T cells secrete a variety of factors to coordinate and stimulate immune responses to specific antigen, such as the role of helper T cells in B cell activation in response to antigen. The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well. Cytokine communication is often local, within a tissue or between cells in close proximity. Each of the cytokines is secreted by one set of cells and provokes a response in another target set of cells, often including the cell that secretes the cytokine. Some cytokines, like IL-1, interferons and TNF, stimulate a broad inflammatory response in response to infection or injury. Other cytokines have more specific functions such the following examples. IL-2 stimulates the proliferation and activation of B and T cells. IL-4 plays a role in the differentiation of Th2 cells, in allergic responses, and in the switching of antibody types. IL-5 stimulates the production and maturation of eosinophils during inflammation. IL-8 is a chemokine, a chemotactic factor that attracts neutrophils, basophils and T cells to sites of inflammation. IL-12 and IL-18 are involved in helper T cell differentiation. IL-10 apparently acts to repress secretion of proinflammatory cytokines. The complex interplay of these different cytokine functions with immune cells is essential for correct immune function. More...
CDMAC_PATHWAY	cdmac pathway	Cadmium induces DNA synthesis and proliferation in macrophages	Exposure to divalent cadmium ions (Cd2+) is a known cancer r...... Exposure to divalent cadmium ions (Cd2+) is a known cancer risk factor, but the molecular mechanisms responsible for the inappropriate induction of cellular proliferation by cadmium are still being figured out. One cellular model used to study this process is macrophages grown in culture. In cultured macrophages, cadmium acts both at the cell surface and in the cytoplasm to induce proliferation. At the cell surface, cadmium interacts with a pertussis-sensitive cell surface receptor, probably a Gi-coupled GPCR, to stimulate proliferation. Cadmium can enter cells through calcium ion channels and once in cells affects calcium release by the ER. In addition to changes in intracellular calcium, the proliferative effects of cadmium are mediated by the Ras/Map kinase pathway, and also NF-kB. Inhibition of phospholipase C, map kinases, or NF-kB with a variety of pharmacological inhibitors all blocked the activation of cellular proliferation by cadmium. Protein kinase C is also activated by cadmium, upstream of the Map kinase pathway. Changes in transcription induced by cadmium include induction of immediate early genes like fos, jun, and myc. In addition to inducing cellular proliferation, cadmium also is slightly genotoxic due to inhibition of DNA repair, activates stress genes, and inhibits the immune system. The immuno-modulatory effects observed with cadmium treatment may also involvement transcriptional disregulation, including the expression of cytokines such as IL-4, IL-10, and TNF-alpha. Although macrophages have been used for many studies, other cell types are also the target of cadmiums toxicity. More...
INFLAM_PATHWAY	inflam pathway	Cytokines and Inflammatory Response	Inflammation is a protective response to infection by the im...... Inflammation is a protective response to infection by the immune system that requires communication between different classes of immune cells to coordinate their actions. Acute inflammation is an important part of the immune response, but chronic inappropriate inflammation can lead to destruction of tissues in autoimmune disorders and perhaps neurodegenerative or cardiovascular disease. Secreted cytokine proteins provide signals between immune cells to coordinate the inflammatory response. Some cytokines such as IL-1, IL-6 and TNF act to broadly provoke the inflammatory response while others act on specific types of immune cells. Macrophages and other phagocytotic cells provide a front-line defense against bacterial infection. Macrophages stimulate the inflammatory responses of neutrophils, fibroblasts, and endothelial cells in response infection by secreting IL-1 and TNF. IL-1 and TNF cause fever through alteration of the body temperature set-point in the hypothalamus. Fibroblasts and endothelial cells respond to IL-1 and TNF by recruiting more immune cells to the site of inflammation. Secreted IL-8 is a chemokine that attracts neutrophils to sites of infection. Macrophages also present antigen to T helper cells that play a central role in coordinating immune responses. T helper cells induce clonal expansion of T cells that respond to antigen, with IL-2 as a key mediator of T cell proliferation and activation. TGF-beta is a negative regulator of proliferation in many cells, have anti-inflammatory actions in some settings. The cytotoxic activity of Natural Killer cells (NK cells) and lymphokine activated killer cells (LAK cells) toward viral infected or tumor cells is stimulated by IL-2 and other cytokines. T helpers secrete IL-3 and IL-5 to stimulate eosinophil proliferation and activation. Eosinophils are involved in the immune response to parasitic infection. T helper cells are required to stimulate B cell responses as well, with the cytokines IL-10, IL-4 and other cytokines regulating the clonal selection and differentiation of antigen-specific B cells to form antibody-secreting plasma B cells and memory cells. In addition to inducing activation and proliferation of specific differentiated immune cells, cytokines act on hematopoeitic stem cells, causing their proliferation and differentiation into the full range of immune cells. More...
PML_PATHWAY	pml pathway	Regulation of transcriptional activity by PML	The PML nuclear bodies are ring-shaped nuclear substructures...... The PML nuclear bodies are ring-shaped nuclear substructures associated with the regulation of transcription, transformation, cell growth, and apoptosis and are characterized by the presence of the protein PML. The activities of PML as a tumor suppressor and apoptosis inducing factor are exerted through the numerous proteins it interacts with in the PML-nuclear bodies including the tumor suppressor p53. DNA damage induced activation of p53-dependent apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP. This acetylation of p53 is reversed by the deacetylase SirT1, the human homolog of the yeast gene Sir2, and this deacetylation opposes the transcriptional activation of p53. The tumor suppressor Rb also interacts with the PML nuclear body, increasing transcriptional repression of genes involved in cell cycle progression, suggesting that PML may affect cellular transformation through more than one mechanism. PML interacts directly with Ubc9, which modifies PML through the attachment of the ubiquitin-like peptide Sumo-1. Sumo-1 modification of PML is not necessary for the nuclear bodies to form, but may affect the recruitment of proteins that interact with PML. PML is involved in non-p53 mediated apoptotic pathways, such as DAXX-mediated apoptosis induced by Fas and TNF and regulates the transcriptional repressor activity of Daxx. The sequestration of Daxx by the PML nuclear bodies relieves the repression of other transcription factors like Pax3 by Daxx. Tumor suppression by PML may in general involve the formation of specific regulatory transcription complexes, including those with DAXX, p53 and CBP. Factors that affect the assembly of PML into the PML nuclear bodies affect the proliferation and transformation of cells. Viral early proteins can interact with PML to disrupt the nuclear bodies, allowing increased proliferation of cells and reduced apoptosis, good conditions for DNA virus infection. Another factor that disrupts the formation of PML nuclear bodies is a translocation between the PML and RAR-alpha genes found in acute promyelocytic leukemia (APL) patients. Binding of retinoic acid to the RAR-alpha steroid hormone receptor activates transcription of retinoic-acid responsive genes. The translocation found in APL patients creates two chimeric proteins, RARalpha-PML and PML-RARalpha. Retinoic acid given to APL patients causes the reappearance of nuclear bodies, and the reversal of cellular transformation, effecting a cure for these patients. More...
TNFR1_PATHWAY	tnfr1 pathway	TNFR1 Signaling Pathway	TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) an...... TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) and also will bind TNF(beta). Upon binding TNF(alpha) a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteins. More...
FREE_PATHWAY	free pathway	Free Radical Induced Apoptosis	Oxidative stress is one factor that can trigger programmed c...... Oxidative stress is one factor that can trigger programmed cell death. Activated neutrophils responding to inflammatory stimulation produce reactive oxygen species like superoxide free radicals to kill invading bacteria, but these reactive oxygen species can also attack endothelial cells lining the vascular wall and trigger apoptosis. Endothelial cells also produce reactive oxygen species inside the cell that can contribute to oxidative stress and apoptosis, such as during reperfusion injury following ischemia. Superoxide dismutase (SOD) converts highly reactive and damaging superoxide free radicals to peroxides that are less reactive than superoxide but stimulate apoptosis. The glutathione (GSH) peptide reducing agent removes toxic metabolites and repairs damage created by reactive oxygen species. Glutathione peroxidase (GPx), for example, removes peroxides using glutathione as a reducing agent, and glutathione reductase (GSR) regenerates reduced glutathione. Inside the endothelial cell peroxide can be converted to hydroxyl ions in the presence of iron. Peroxides and hydroxyl radicals activate NF-kB and activate expression of inflammatory genes including adhesion molecules, TNF and IL-8. The apoptotic response of endothelial cells to oxidative stress may be involved in the development and progression of atherosclerosis. More...
LAIR_PATHWAY	lair pathway	Cells and Molecules involved in local acute inflammatory response	Inflammation has several distinct components, including the ...... Inflammation has several distinct components, including the localized response at the site of tissue injury or infection. Tissue injury stimulates the release of inflammatory signaling molecules such as bradykinin. Bacterial infection stimulates an immune response in several ways. Bacteria that are phagocytosed can activate macrophages, causing the release of inflammatory cytokines such as IL-1, TNF, and IL-6. Bacteria can also activate the complement cascade through either the antibody-mediated pathway (classical pathway) or the alternative complement pathway. In extravascular tissues, cells that respond to infection or injury include macrophages and mast cells. Macrophages and other immune cells secrete chemokines that recruit leukocytes from the circulation to the site of inflammation. Mast cells release histamine, prostaglandins, and leukotrienes that act as chemokines, increase vascular permeability, and act on the vascular endothelium to increase tissue recruitment of leukocytes. Chemokines can recruit leukocytes or lymphocytes out of the blood stream into tissues and make blood vessels more permeable. Leukocytes are activated by inflammatory signals to express adhesion molecules that cause them to interact with the vascular endothelium, penetrate the endothelial wall and migrate into the extracellular space of tissues. The combined response of immune cells and signaling molecules at the site of inflammation induces swelling, activation of immune cells, and clearance of potential infectious agents. Chronic inflammation can however also lead to tissue damage in conditions such as arthritis, in which anti-inflammatory drugs act on various steps in inflammation to prevent disease. More...
TID_PATHWAY	tid pathway	Chaperones modulate interferon Signaling Pathway	Signaling by interferon-gamma stimulates anti-viral response...... Signaling by interferon-gamma stimulates anti-viral responses and tumor suppression through the heterodimeric interferon-gamma receptor. Signaling is initiated by binding of interferon-gamma to its receptor, activating the receptor-associated JAK2 tyrosine kinase to phosphorylate STAT transcription factors that activate interferon responsive genes. Molecular chaperones that modulate or alter protein folding interact with different components of the interferon signaling pathway. One chaperone that modulates interferon signaling is hTid-1, a member of the DnaJ family of chaperones and a cochaperone for the heat shock protein Hsp70, another molecular chaperone. hTid-1 was found in a two-hybrid screen to bind to JAK2 and also to interact with the interferon-gamma receptor. In addition, hTid-1 and JAK2 also interact with Hsp70. Overexpression of hTid-1 represses transcriptional activation by interferon-gamma and Hsp70 dissociates from these proteins when interferon is added to cells, suggesting that Hsp70 holds Jak2 in an inactive conformation prior to ligand activation, and is released in the presence of agonist to allow the activation of Jak-2 and downstream pathways. hTid-1 and Hsp-70 interact with other signaling proteins as well. One of this is Tax, a protein encoded by the HTLV-1 virus that binds to hTid-1. hTid-1 also represses NF-kB activation by blocking the phosphorylation and inactivation of I-kappaB by the IkappaB kinase beta. Hsp70 plays a significant role in protein unfolding for entry into mitochondria and also interacts with tumor suppressor gene products to produce their anti-proliferative activity. One of the actions of interferon is to induce apoptosis of infected target cells, in part through a mitochondrial dependent mechanism. An interaction between interferon signaling and Hsp70 may alter this mitochondrial apoptosis pathway, perhaps playing a role in interferon-mediated apoptosis of infected or transformed cells. The HTLV-1 Tax protein that interacts with Hsp70 blocks mitochondrial induced apoptosis, providing a protection against interferon-mediated cellular defenses. More...
RELA_PATHWAY	rela pathway	Acetylation and Deacetylation of RelA in The Nucleus
STRESS_PATHWAY	stress pathway	TNF/Stress Related Signaling	TNF acts on several different signaling pathways through two...... TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathways leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF. More...
PPARA_PATHWAY	ppara pathway	Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha)	The most recognized mechanism by which peroxisome proliferat...... The most recognized mechanism by which peroxisome proliferators regulated gene expresssion is through a PPAR/RXR heterodimeric complex binding to a peroxisome proliferator-response element (PPRE) (classical mechanism). However, there are the possibility of several variations on this theme: 1). The peroxisome proliferator interacts with PPAR that preexists as a DNA complex with associated corepressors proteins. The interaction with ligand causes release of the corepressor and association with a coactivator, resulting in the classical mechanism. 2). The peroxisome proliferator interacts with PPAR as a soluble member of the nucleus. The binding of ligand results in RXR heterodimerization, DNA binding and coactivator recruitment. 3). In this scenario, PPAR exists in the cytosol, perhaps complexed to heat shock protein 90 and/or other chaperones. Binding of peroxisome proliferator causes a conformational change and translocation into the nucleus. Scenarios 4 and 5 require regulation of gene expression via non-classical mechanisms: 4). PPAR is capable of interacting with, and forming DNA binding heterodimers with, several nuclear receptors including the thyroid hormone receptor. The binding site for this non-RXR heterodimer need not be the classic DR-1 motif found in the PPRE. 5). PPAR may participate in the regulation of gene expression witout binding to DNA. By association with transcription factors such as c-jun or p65, PPAR diminishes the ability of AP1 or NFB to bind to their cognate DNA sequences, respectively. Also shown in this scheme are two means to modify the peroxisome proliferator response. Most importantly, growth factor signaling has a pronounced affect on PPAR via post-translational modification. PPAR is a phosphoprotein and its activity is affected by insulin. Several kinase pathways affects PPARa's activity, although the specific kinases and phosphorylation sites have not been conclusively determined. More...
IL10_PATHWAY	il10 pathway	IL-10 Anti-inflammatory Signaling Pathway	IL-10 is a cytokine with potent anti-inflammatory properties...... IL-10 is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-alpha, IL-6 and IL-1 by activated macrophages. The IL-10 receptor is in the JAK/STAT class of receptors but activation of the JAK/STAT pathways by IL-10 does not appear on its own to be responsible for the anti-inflammatory properties of this cytokine. The anti-inflammatory actions of IL-10 appear to require induction of the enzyme heme oxygenase-1 (HO-1) through a map kinase pathway involving the p38 kinases. HO-1 is involved in the biosynthesis of heme, and catalyzes a reaction producing carbon monoxide, free iron, and the heme precursor biliverdin. HO-1 is induced by IL-10 and is also induced by oxidative stress. Blocking HO-1 with inhibitors or antisense blocks the anti-inflammatory actions of IL-10. The anti-inflammatory actions of HO-1 appear to be the result of signaling by carbon monoxide it produces since removal of CO blocks the anti-inflammatory action of IL-10 and HO-1. The anti-inflammatory actions of IL-10 may be therapeutically useful either directly or through modulation of HO-1 activity. More...
KERATINOCYTE_PATHWAY	keratinocyte pathway	Keratinocyte Differentiation	The epidermis, which provides a protective barrier that unde...... The epidermis, which provides a protective barrier that undergoes a constant renewal, is a multi-layered tissue with the proliferating cells located in the basal layer. As cells leave the basal layer the underog significant differentiation, biochemical and morphological remodeling. The final differentiation results in the formation of corneocytes. In vitro keratinocytes mimic this process. Several genes mark keratinocyte specific differentiation. Among the most frequently tracked markers are Transglutaminase, Cystatin and Involucrin. The keratinocyte differentiation studies have identified and provided significant detail regarding the involvement of three of the 4 major MAP kinase pathways from several diverse stimuli such as EGF, FAS, TNF and Calicium influx. The p38 cascade is represented twice since both p38alpha (p38) and p38delta (MAPK13) are involved. The keratinocyte differentiation cascased also provide for detailed study of the functions of individual PKC isoforms. It is interesting to note the contrasting functions of the PKC isoforms in this process. In recent studies it has been determined that the cPKC (conventional/classical Protein Kinase C) isoforms, which are calcium-, phospholipid-, and diacylglycerol-dependent are inhibitory where as the nPKC (novel Protein Kinase C) isoforms which are calcium independent are stimulatory for keratinocyte differentiation markers. On the right hand side is an earlier step showing the upregulation loop of TRAF2. This step occurs prior to the activation os ASK1 and the p38 cascade. More...
HIVNEF_PATHWAY	hivnef pathway	HIV-I Nef: negative effector of Fas and TNF	HIV infection leads to drastic declines in CD4 T helper cell...... HIV infection leads to drastic declines in CD4 T helper cells, in part through apoptosis of uninfected cells. Apoptosis of uninfected cells may be induced through the expression of Fas ligand on the surface of HIV-infected cells, stimulating the Fas-dependent apoptotic pathway in cells that come in contact with infected cells. The NEF protein expressed by HIV may play induce the expression of Fas-ligand by infected cells. If this is the case, then a question that arises is how infected cells themselves escape Fas-mediated apoptosis. The NEF protein appears to play a role in this process as well. NEF interacts with the ASK1 kinase (apoptosis signal-regulating kinase) involved in apoptotic signaling by TNF and Fas-ligand. Interaction of NEF with ASK1 prevents phosphorylation of downstream MAP kinases and JNK kinases involved in apoptotic signaling. More...
GRANULOCYTES_PATHWAY	granulocytes pathway	Adhesion and Diapedesis of Granulocytes	Cell adhesion is a fundamental feature of multicellular orga...... Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play central role. They bind bacteria, parasites, viruses, tumor cells etc. Furthermore, their interactions with the endothelium are of special importance. During an inflammation or immune reaction, specialized leukocytes (eosinophilic granulocytes) adhere to and pass through the endothelium of the blood vessels and the underlying matrix. The reaction passes through the following steps: 1. Rolling (the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors); 2. Adhesion (After activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily - LFA-1, Mac-1, VLA-4 etc.); 3. Flattening of the cells and diapedesis (Adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by a homophilic interactions of PECAM and CD31. More...
IL1R_PATHWAY	il1r pathway	Signal transduction through IL1R	Interleukin-1 (IL-1) is a pro-inflammatory cytokine that sig...... Interleukin-1 (IL-1) is a pro-inflammatory cytokine that signals primarily through the type 1 IL-1 receptor (IL-1R1). The activities of IL-1 include induction of fever, expression of vascular adhesion molecules, and roles in arthritis and septic shock. The inflammatory activities of IL-1 are partially derived by transcriptionally inducing expression of cytokines such as TNF-alpha and interferons, as well as inducing the expression of other inflammation-related genes. There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 beta is produced as a 269 amino acid precursor that is cleaved by IL-1beta converting enzyme (ICE) to the active IL-1 beta form that is secreted. IL-1 signaling is opposed by the naturally occurring peptide IL-1 receptor antagonist which is a therapeutic agent for the treatment of arthritis. The type 1 IL-1 receptor protein binds IL-1 beta but requires the IL-1 receptor accessory protein (IL-1RAcP) to transduce a signal. IL-1 binding causes activation of two kinases, IRAK-1 and IRAK-2, associated with the IL-1 receptor complex. IRAK-1 (IL-1 Receptor Associated Kinase) activates and recruits TRAF6 to the IL-1 receptor complex. TRAF6 activates two pathways, one leading to NF-kB activation and another leading to c-jun activation. The TRAF associated protein ECSIT leads to c-Jun activation through the Map kinase/JNK signaling system. TRAF6 also signals through the TAB1/TAK1 kinases to trigger the degradation of I-kB, and activation of NF-kB. The IL-1 signaling cascade represents a highly conserved response to pathogens through evolution, with homologs in insects and even in plants. The signal transduction cascade utilized by IL-1 receptor is similar to that of TNF, resulting in NF-kB activation, and is most similar to that of the Toll-like receptors that also participate in inflammatory signaling responses to pathogen components like endotoxin. More...
HSP27_PATHWAY	hsp27 pathway	Stress Induction of HSP Regulation	Mammalian cells can respond to a variety of stresses such as...... Mammalian cells can respond to a variety of stresses such as heat, cold, oxidative stress, metabolic disturbance, and environmental toxins through necrotic or apoptotic cell death, while increased expression and phosphorylation of heat shock proteins such as Hsp27 can protect cells against cellular stress. Heat shock proteins commonly exhibit molecular chaperone activity and also interact with a wide variety of proteins to exert specific effects. The small heat shock protein Hsp27 exists as monomers, dimers, and oligomers in the cell, and each form has distinct activities. Oligomers are the main form of Hsp27 with molecular chaperone activity and are disrupted by phosphorylation of Hsp27 to form dimers and monomers. S-thiolation of Hsp27 on cysteine also dissociates oligomers and may provide another route of regulating the action of Hsp27 in stress. Map kinase cascades mediate Hsp27 phosphorylation. Heat stress activates the p38 kinase cascade and induces phosphorylation of Hsp27 by the downstream Map kinases Mapkapk2 and Mapkap3. Cytokines such as TNF and IL-1 can also induce Hsp27 phoshorylation through this Map kinase cascade, protecting cells in some settings against cytotoxic responses. In stressful conditions, dissociation of oligomeric Hsp27 by phosphorylation may allow lower molecular weight forms to perform other non-chaperone functions. One action of Hsp27 induced by stress is to protect cells against apoptosis and a common component of apoptotic pathways is the mitochondrial release of cytochrome c. One way that Hsp27 reduces apoptosis is by preventing the release of cytochrome c and by binding to cytochrome c in the cytosol. Downstream, Hsp27 also blocks caspase 9 activation and the subsequent activation of caspase 3, inhibiting the rest of the proteolytic caspase cascade. Yet a further role of Hsp27 in blocking apoptosis is through blocking Fas-induced apoptosis. Fas is a receptor in the TNF receptor gene family that induces apoptosis when stimulated by its cell-bound ligand, Fas-ligand. Fas induces apoptosis through two pathways, one mediated by the protein Daxx. Phosphorylated Hsp27 dimers block apoptosis by binding with Daxx and preventing downstream activation of the kinase Ask1. The interaction of Hsp27 with actin filaments may also prevent apoptosis triggered by some agents like staurosporine that damage actin. Unphosphorylated Hsp27 monomers regulate actin filament growth by binding to the end of fibers and capping them. Finally, Hsp27 appears to prevent damage to cells by reactive oxygen species (ROS), by altering the oxidative environment of the cell through induction of glutathione expression, as well as blocking apoptosis induced by ROS. Modulation of Hsp27 expression and phosphorylation may provide a useful means to alter cellular sensitivity to stress. More...
NFKB_PATHWAY	nfkb pathway	NF-kB Signaling Pathway	Nuclear factor kB (NF-kB) is a nuclear transcription factor ...... Nuclear factor kB (NF-kB) is a nuclear transcription factor that regulates expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases. The activation of NF-kB is thought to be part of a stress response as it is activated by a variety of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological agents, and stress. In its inactive form, NF-kB is sequestered in the cytoplasm, bound by members of the IkB family of inhibitor proteins, which include IkBa, IkBb, IkBg, and IkBe. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. This results in the exposure of the nuclear localization signals (NLS) on NF-kB subunits and the subsequent translocation of the molecule to the nucleus. In the nucleus, NF-kB binds with a consensus sequence (5'GGGACTTTCC-3') of various genes and thus activates their transcription. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins; IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB leading to its ubiquitination and degradation. Tumor necrosis factor (TNF) which is the best-studied activator binds to its receptor and recruits a protein called TNF receptor death domain (TRADD). TRADD binds to the TNF receptor-associated factor 2 (TRAF-2) that recruits NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP kinase NIK/MEKK1 and both kinases can independently phosphorylate IkBa or IkBb. TRAF-2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-kB suggesting that it may act as a general inhibitor of NF-kB activation. More...

TNF related Reactome pathways (count: 2)

ID	Name	Description
Gene mapped Reactome pathways
REACT_1619	death receptor_signalling	The death receptors, all cell-surface receptors, begin the p...... The death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the death-domain a conserved cytoplasmic motif found on all of the three receptors (FAS/CD95, TNF-receptor, and TRAIL-receptor) that binds the Fas-associated protein with death domain (FADD) More...
REACT_578	apoptosis	Apoptosis is a distinct form of cell death that is functiona...... Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and membrane blebbing characterize apoptosis in general. Mitochondria remain morphologically unchanged. In 1972 Kerr et al introduced the concept of apoptosis as a distinct form of cell-death, and the mechanisms of various apoptotic pathways are still being revealed today. The two principal pathways of apoptosis are (1) the Bcl-2 inhibitable or intrinsic pathway induced by various forms of stress like intracellular damage, developmental cues, and external stimuli and (2) the caspase 8/10 dependent or extrinsic pathway initiated by the engagement of death receptors The caspase 8/10 dependent or extrinsic pathway is a death receptor mediated mechanism that results in the activation of caspase-8 and caspase-10. Activation of death receptors like Fas/CD95, TNFR1, and the TRAIL receptor is promoted by the TNF family of ligands including FASL (APO1L OR CD95L), TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, BLYS/BAFF, and APO2L/TRAIL. These ligands are released in response to microbial infection, or as part of the cellular, humoral immunity responses during the formation of lymphoid organs, activation of dendritic cells, stimulation or survival of T, B, and natural killer (NK) cells, cytotoxic response to viral infection or oncogenic transformation. The Bcl-2 inhibitable or intrinsic pathway of apoptosis is a stress-inducible process, and acts through the activation of caspase-9 via Apaf-1 and cytochrome c. The rupture of the mitochondrial membrane, a rapid process involving some of the Bcl-2 family proteins, releases these molecules into the cytoplasm. Examples of cellular processes that may induce the intrinsic pathway in response to various damage signals include: auto reactivity in lymphocytes, cytokine deprivation, calcium flux or cellular damage by cytotoxic drugs like taxol, deprivation of nutrients like glucose and growth factors like EGF, anoikis, transactivation of target genes by tumor suppressors including p53. In many non-immune cells, death signals initiated by the extrinsic pathway are amplified by connections to the intrinsic pathway. The connecting link appears to be the truncated BID (tBID) protein a proteolytic cleavage product mediated by caspase-8 or other enzymes. More...

TNF related interactors from protein-protein interaction data in HPRD (count: 13)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
TNF	ADAM17	No	in vitro;in vivo	12135369 , 10799478
TNF	TRAF2	No	in vivo	12887920
TNF	MMP17	No	in vitro	10799478
TNF	TNFRSF1A	Yes	in vitro;in vivo	10634209 , 14743216 , 19084540
TNF	DCN	No	in vitro	12387878
TNF	BGN	No	in vitro	12387878
TNF	PRTN3	No	in vivo	10339575
TNF	TNFRSF1B	Yes	in vitro;in vivo	7664431 , 2158863 , 19084540
TNF	TNF	Yes	in vitro	2551905 , 2922050 , 3351931 , 3417634 , 8869635 , 9442056 , 9488135
TNF	ADAM9	No	in vitro	9920899
TNF	PDIK1L	No	in vitro;in vivo	8597870
TNF	IFNG	Yes	in vitro;in vivo	3139842
TNF	CSF1	No	in vivo	8336080

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Literature-origin BioCarta pathway

Gene mapped BioCarta pathways

Gene mapped Reactome pathways