Specifically, single nucleotide polymorphisms (SNPs) in two ......
Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome beta4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation.More...
Positive relationships between PSMB4 and other components at different levels (count: 0)
Positive relationship network of PSMB4 in MK4MDD
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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
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If the mapped gene or protein is not from literature, square node would be used instead of Circle node.
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Negative relationships between PSMB4 and MDD (count: 0)
Negative relationships between PSMB4 and other components at different levels (count: 0)
The proteasome is a protein-destroying apparatus involved in......
The proteasome is a protein-destroying apparatus involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. It is capable of degrading a variety of cellular proteins in a rapid and timely fashion and most substrate proteins are modified by ubiquitin before their degradation by the proteasome. The proteasome is a large protein complex consisting of a proteolytic core called the 20S particle and ancillary factors that regulate its activity in various ways. The most common form is the 26S proteasome containing one 20S core particle and two 19S regulatory particles that enable the proteasome to degrade ubiquitinated proteins by an ATP-dependent mechanism. Another form is the immunoproteasome containing two 11S regulatory particles, PA28 alpha and PA28 beta, which are induced by interferon gamma under the conditions of intensified immune response. Other regulatory particles include PA28 gamma and PA200. Although PA28 gamma also belongs to a family of activators of the 20S proteasome, it is localized within the nucleus and forms a homoheptamer. PA28 gamma has been implicated in the regulation of cell cycle progression and apoptosis. PA200 has been identified as a large nuclear protein that stimulates proteasomal hydrolysis of peptides.More...
Attachment of the ubiquitin peptide to proteins targets them......
Attachment of the ubiquitin peptide to proteins targets them for proteolytic degradation by a complex cellular structure, the proteasome. The regulated proteolysis of proteins by proteasomes removes denatured, damaged or improperly translated proteins from cells and regulates the level of proteins like cyclins or some transcription factors. E1 and E2 enzymes prepare ubiquitin chains that are then attached to proteins by the E3 enzyme. The sequence of ubiquitin and the basic structure and function of the proteasome are highly conserved. The core proteasome in man (20S proteasome) consists of four rings each with 14 subunits stacked on top of each other that are responsible for the proteolytic activity of the proteasome. The PA700 regulatory complex is stacked on the ends of the cylindrical core to form a 26S proteasome. Proteins that are tagged with ubiquitin are recognized and bound by the regulatory subunits, then unfolded in an ATP-dependent manner, and inserted into the core particle, where proteases degrade the protein, releasing small peptides and releasing the ubiquitin intact. The PA28 regulatory complex is alternative regulatory complex that appears to play a role in antigen processing for presentation of peptides to immune cells in the MHC I complex.More...
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...
Like all viruses, HIV-1 must co-opt the host cell macromolec......
Like all viruses, HIV-1 must co-opt the host cell macromolecular transport and processing machinery. HIV-1 Vpr and Rev proteins play key roles in this co-optation. Efficient HIV-1 replication likewise requires evasion of APOBEC3G-mediated mutagenesis of reverse transcripts, a process mediated by the viral Vif protein.More...
Later studies pin-pointed that a single serine. ATM also reg......
Later studies pin-pointed that a single serine. ATM also regulates the phosphorylation of p53 at other sites, especially Ser-20, by activating other serine/threonine kinases in response to IR. Phosphorylation of p53 at Ser-20 interferes with p53-MDM2 interaction. MDM2 is transcriptionally activated by p53 and is a negative regulator of p53 that targets it for degradation. In addition modification of MDM2 by ATM also affects p53 stabilization.More...
Cyclin E - Cdk2 complexes control the transition from G1 int......
Cyclin E - Cdk2 complexes control the transition from G1 into S-phase. In this case, the binding of p21Cip1/Waf1 or p27kip1 is inhibitory. Important substrates for Cyclin E - Cdk2 complexes include proteins involved in the initiation of DNA replication. The two Cyclin E proteins are subjected to ubiquitin-dependent proteolysis, under the control of an E3 ubiquitin ligase known as the SCF. Cyclin A - Cdk2 complexes, which are also regulated by p21Cip1/Waf1 and p27kip1, are likely to be important for continued DNA synthesis, and progression into G2. An additional level of control of Cdk2 is reversible phosphorylation of Threonine-14 (T14) and Tyrosine-15 (Y15), catalyzed by the Wee1 and Myt1 kinases, and dephosphorylated by the three Cdc25 phosphatases, Cdc25A, B and C.More...
The transition from the G1 to S phase is controlled by the C......
The transition from the G1 to S phase is controlled by the Cyclin E:Cdk2 complexes. As the Cyclin E:Cdk2 complexes are formed, the Cdk2 is phosphorylated by the Wee1 and Myt1 kinases. This phosphorylation keeps the Cdk2 inactive. In yeast this control is called the cell size checkpoint control. The dephosphorylation of the Cdk2 by Cdc25A activates the Cdk2, and is coordinated with the cells reaching the proper size, and with the DNA synthesis machinery being ready. The Cdk2 then phosphorylates G1/S specific proteins, including proteins required for DNA replication initiation. The beginning of S-phase is marked by the first nucleotide being laid down on the primer during DNA replication at the early-firing originsMore...
During G1, the activity of cyclin-dependent kinases. These t......
During G1, the activity of cyclin-dependent kinases. These two CKIs are degraded in late G1 phase by the ubiquitin pathway involving the ubiquitin ligase SCF and the cell-cycle regulatory protein Cks1. Recognition of p27 by SCF. There is evidence that Cyclin A/B:Cdk1 complexes can also bind and phosphorylate p27 on Th187. Degradation of polyubiquitinated p27 by the 26S proteasome promotes the activity of CDKs in driving cells into S phase.. The mechanism of SCF. In addition, as observed for p27, p21 phosphorylation at a specific site. SCF. The tight regulation of APC/C. Inhibition of APC/C. Finally, to make the inactivation of APC/C. At G1/S, Skp2 reaccumulates as Cdh1 is inactivated, thus allowing the ubiquitination of p21 and p27 and resulting in a further increase in CDK activity.More...
Initiation protein Cdt1 was first identified in X. laevis, w......
Initiation protein Cdt1 was first identified in X. laevis, where it has been shown to be the second component of licensing factor (RLF-B) and in S. pombe. Cdt1 homologs have been identified in D. melanogaster, humans, and S. cerevisiae. Genetic studies in S. pombe have shown that binding of Cdc6 to chromatin requires the prior binding of Cdc18, the S. pombe homolog of Cdc6. In humans, the function of CDT1 is regulated during the cell cycle by its tight association with an inhibitory factor, geminin.More...
Emi1 destruction in early mitosis requires the SCFTrCP ubiqu......
Emi1 destruction in early mitosis requires the SCFTrCP ubiquitin ligase complex. Binding of TrCP to Emi1 occurs in late prophase and requires phosphorylation at the DSGxxS consensus motif as well as Cdk mediated phosphorylation. A two-step mechanism has been proposed in which the phosphorylation of Emi1 by Cdc2 occurs after the G2-M transition followed soon after by binding of TrCP to the DSGxxS phosphorylation sites. Emi1 is then poly-ubiquitinated and degraded by the 26S proteasome.More...
DNA synthesis occurs in the S phase, or the synthesis phase,......
DNA synthesis occurs in the S phase, or the synthesis phase, of the cell cycle. The cell duplicates its hereditary material, and two copies of the chromosome are formed. As DNA replication continues, the E type cyclins shared by the G1 and S phases, are destroyed and the levels of the mitotic cyclins rise.More...
The global pandemic of Human Immunodeficiency Virus. HIV-1 a......
The global pandemic of Human Immunodeficiency Virus. HIV-1 and the less common HIV-2 belong to the family of retroviruses. HIV-1 contains a single-stranded RNA genome that is 9 kilobases in length and contains 9 genes that encode 15 different proteins. These proteins are classified as: structural proteins. HIV infection cycle can be divided into two phases: 1. An Early phase consisting of early events occuring after HIV infection of a susceptible target cell and a 2. Late phase comprising the later events in the HIV-infected cell resulting in the assembly of new infectious virions. The section titled HIV lifecycle consists of annotations of events in these two phases. The virus has developed various molecular strategies to suppress the antiviral immune responses. The section titled Host interactions of HIV factors will highlight these complex post-infection processes and the annotations will be released in near future.More...
Cdh1 is degraded by the APC/C during in G1 and G0. This auto......
Cdh1 is degraded by the APC/C during in G1 and G0. This auto-regulation may contribute to reducing the levels of Cdh1 levels during G1 and G0.More...
Polyamines increase the production of antizyme. The followin......
Polyamines increase the production of antizyme. The following illustration is adapted from a minireview by Pegg, 2006; J. Biol. Chem., Vol. 281, Issue 21, 14529-14532.More...
The actual synthesis of DNA occurs in the S phase of the cel......
The actual synthesis of DNA occurs in the S phase of the cell cycle. This includes the initiation of DNA replication, when the first nucleotide of the new strand is laid down during the synthesis of the primer. The DNA replication preinitiation events begin in late M or early G1 phase.More...
The HIV-1 accessory protein Vif. Deamination changes cytidin......
The HIV-1 accessory protein Vif. Deamination changes cytidine to uracil and thus results in G to A transitions and stop codons in the provirus. The aberrant cDNAs produced in the infected cell can either be integrated in form of non-functional proviruses or degraded. Vif counteracts the antiviral activity of APOBEC3G by associating directly with it and promoting its polyubiquitination and degradation by the 26S proteasome. Vif binds APOBEC3G and recruits it into an E3 ubiquitin-enzyme complex composed by the cytoplasmic proteins Cullin5, Rbx, ElonginC and ElonginB. Thus, in the presence of Vif, APOBEC3G incorporation into the virion is minimal.More...
The replication of the genome and the subsequent segregation......
The replication of the genome and the subsequent segregation of chromosomes into daughter cells are controlled by a series of events collectively known as the cell cycle. DNA replication is carried out during a discrete temporal period known as the S (synthesis)-phase, and chromosome segregation occurs during a massive reorganization to cellular architecture at mitosis. Two gap-phases separate these major cell cycle events: G1 between mitosis and S-phase, and G2 between S-phase and mitosis. In the development of the human body, cells can exit the cell cycle for a period and enter a quiescent state known as G0, or terminally differentiate into cells that will not divide again, but undergo morphological development to carry out the wide variety of specialized functions of individual tissues. A family of protein serine/threonine kinases known as the cyclin-dependent kinases (CDKs) controls progression through the cell cycle. As the name suggests, the activity of the catalytic subunit is dependent on binding to a cyclin partner. The human genome encodes several cyclins and several CDKs, with their names largely derived from the order in which they were identified. The oscillation of cyclin abundance is one important mechanism by which these enzymes phosphorylate key substrates to promote events at the relevant time and place. Additional regulatory proteins and post-translational modifications ensure that CDK activity is precisely regulated, frequently confined to a narrow window of activity.More...
Although, DNA replication occurs in the S phase of the cell ......
Although, DNA replication occurs in the S phase of the cell cycle, the formation of the DNA replication pre-initiation complex begins during late G1/M transition.More...
Cyclin A, functions in mitosis as well as DNA replication an......
Cyclin A, functions in mitosis as well as DNA replication and is degraded in the interim by the APC/C to permit normal chromosome segregation, cell division, and the onset of S phase. Cyclin A is initially degraded early in mitosis by APC/C:Cdc20 when the spindle checkpoint is still active and degradation of securin and cyclin B is inhibited.More...
This group of reactions is responsible for: 1) the breakdown......
This group of reactions is responsible for: 1) the breakdown of amino acids; 2) the synthesis of urea from ammonia and amino groups generated by amino acid breakdown; 3) the synthesis of the ten amino acids that are not essential components of the human diet; and 4) the synthesis of related nitrogen-containing molecules including carnitine and creatine.More...
The beta-catenin destruction complex plays a key role in the......
The beta-catenin destruction complex plays a key role in the canonical Wnt signaling pathway. In the absence of Wnt signaling, this complex controls the levels of cytoplamic beta-catenin. Beta-catenin associates with and is phosphorylated by the destruction complex. Phosphorylated beta-catenin is recognized and ubiquitinated by the SCF-beta TrCP ubiquitin ligase complex and is subsequently degraded by the proteasome.More...
A hallmark of the human cell cycle in normal somatic cells i......
A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation. Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs. The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear.More...
The APC/C is activated by either Cdc20 or Cdh1. While both a......
The APC/C is activated by either Cdc20 or Cdh1. While both activators associate with the APC/C, they do so at different points in the cell cycle and their binding is regulated differently. Cdc20, whose protein levels increase as cells enter into mitosis and decrease upon mitotic exit, only associates with the APC/C during M phase. Cdh1 associates with the APC/C in G1. This interaction is inhibited at other times by Cdk1 phosphorylation.More...
In response to DNA damage due to exposure to ultraviolet lig......
In response to DNA damage due to exposure to ultraviolet light or to ionizing radiation, Cdc25A is phosphorylated by Chk1 or Chk2. The phosphorylation of Cdc25A at ser-123, in response to DNA damage from ionizing radiation is a signal for ubiquitination and subsequent degradation of Cdc25A. The destruction of Cdc25A prevents the normal G1/S transition. Cdc25A is required for the activation of the Cyclin E:Cdk2 complexes via dephosphorylation. Chk1 is activated in response to DNA damage due to uv light. However, the phosphorylation occurs at a different site.More...
Finally, progression out of mitosis and division of the cell......
Finally, progression out of mitosis and division of the cell into two daughters (cytokinesis) requires the inactivation of Cyclin B - Cdc2 by ubiquitin-dependent proteolysis of Cyclin A and B, which is regulated by a large E3 ubiquitin ligase complex known as the Anaphase Promoting Complex (APC). The detailed annotation of the M/G1 transition will be completed in a later version of GK.More...
Basic Information
Positive relationships between PSMB4 and other components at different levels (count: 0)
