Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor protein is a highly potent transcription factor which, under normal circumstances, is maintained at low levels through the action of MDM2, an E3 ubiquitin ligase which directs p53 ubiquitylation and degradation. Expression of the mdm2 gene is stimulated by p53 and this reciprocal relationship forms the basis of a negative feedback loop. Both genotoxic and non-genotoxic stresses that induce p53 focus principally on interruption of the p53-MDM2 loop with the consequence that p53 becomes stabilised, leading to changes in the expression of p53-responsive genes. The biological outcome of inducing this pathway can be either growth arrest or apoptosis: factors affecting the functioning of the loop, the biochemical activity of p53 itself and the cellular environment govern the choice between these outcomes in a cell type- and stress-specific manner.
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PMID:The p53 response to DNA damage. 1527 92

The von Hippel-Lindau (VHL) tumour suppressor gene encodes a substrate-specifying component of an E3 ubiquitin ligase that targets hypoxia-inducible factor (HIF) alpha subunits for degradation under normoxia. The VHL protein is composed of an N-terminal HIFalpha-binding beta domain and a C-terminal alpha domain, which is necessary and sufficient for the formation of the E3 multiprotein enzyme. A large number of disease-causing mutations in either the alpha or beta domain renders HIFalpha stable irrespective of oxygen tension, leading to the upregulation of numerous HIF-target genes, such as GLUT1 and VEGF. Here, we show that VHL forms a self-associated complex in vivo, but not in vitro, and demonstrate that coexpression of two different VHL missense mutants -- one in the alpha domain and the other in the beta domain -- restores HIF-mediated gene expression profile. These findings indicate that VHL homotypic complexes can function in vivo in a complementary fashion to target HIFalpha for ubiquitin-mediated proteolysis, and potentially explain why VHL-associated tumours with a missense mutation-carrying VHL allele is almost invariably accompanied by a second VHL allele harbouring a gross truncation or deletion.
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PMID:Homotypic association between tumour-associated VHL proteins leads to the restoration of HIF pathway. 1640 35

Signal transducers and activators of transcription (STATs) comprise a family of several transcription factors that are activated by a variety of cytokines, hormones and growth factors. STATs are activated through tyrosine phosphorylation, mainly by JAK kinases, which lead to their dimerization, nuclear translocation and regulation of target genes expression. Stringent mechanisms of signal attenuation are essential for insuring appropriate, controlled cellular responses. Among them phosphotyrosine phosphatases (SHPs, CD45, PTP1B/TC-PTP), protein inhibitors of activated STATs (PIAS) and suppressors of cytokine signaling (SOCS) inhibit specific and distinct aspects of cytokine signal transduction. SOCS proteins bind through their SH2 domain to phosphotyrosine residues in either cytokine receptors or JAK and thus can suppress cytokine signaling. Many recent findings indicate that SOCS proteins act, in addition, as adaptors that regulate the turnover of certain substrates by interacting with and activating an E3 ubiquitin ligase. Thus, SOCS proteins act as negative regulators of JAK/STAT pathways and may represent tumour suppressor genes. The discovery of oncogenic partner in this signaling pathway, more especially in diverse hematologic malignancies support a prominent role of deregulated pathways in the pathogenesis of diseases. Fusion proteins implicating the JH1 domain of JAK2 (TEL-JAK2, BCR-JAK2), leading to deregulated activity of JAK2, have been described as the result of translocation. Somatic point mutation in JH2 domain of JAK2 (JAK2V617F), leading also to constitutive tyrosine phosphorylation of JAK2 and its downstream effectors was reported in myeloproliferative disorders. Furthermore, silencing of socs-1 and shp-1 expression by gene methylation is observed in some cancer cells.
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PMID:JAK/STAT signal transduction: regulators and implication in hematological malignancies. 1642 81

Hypoxia-inducible factor 1alpha (HIF-1alpha) degradation under normoxia is critical to modulating vascular growth. This degradation is mediated during normoxia by the von Hippel-Lindau tumour suppressor protein (VHL)-E3 ubiquitin ligase in partnership with the E2 enzyme UbcH5. In current models of the functionally similar Skp1, cullin, F-box (SCF)-E3 ligase, the E3 binds the target protein and the E2 catalyses ubiquitin transfer to lysines in an appropriately positioned domain. In the present study, we report that for efficient ubiquitination of HIF-1alpha to occur, three conserved lysines are required in both the HIF-1alpha and endothelial Per-ARNT-Sim domain protein (EPAS) sequences. The site of ubiquitin attachment via UbcH5 was mapped, and is shown to involve three HIF-1alpha lysines, K532, K538 and K547, and the same aligned lysines in EPAS. Only one of these lysines need to be intact for full ubiquitination to occur, analogous to the mechanism of Sic1 ubiquitination by the SCF/Cdc34 complex and further strengthening the functional link between the VHL and SCF-E3 ubiquitin ligases. We also report that lysines can be moved around the HIF-1alpha sequence with only minor losses in ubiquitination efficiency, thus suggesting HIF-1alpha and EPAS regulation by hypoxia depends primarily on an interaction with VHL per se, rather than the highly specific positioning of flanking lysine acceptors.
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PMID:HIF-1alpha and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases. 1686 77

Ubiquitylation is an important regulatory mechanism of many cellular processes. The breast and ovarian cancer-specific tumour suppressor BRCA1 is well acknowledged to be a RING/E3 ubiquitin ligase, however, identification of its physiological substrates has proved elusive. Recently published data have shown that the BRCA1-interacting protein CtIP is in fact ubiquitylated by BRCA1, and opens new avenues for the isolation of other substrate proteins.
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PMID:BRCA1 ubiquitylation of CtIP: Just the tIP of the iceberg? 1702 45

The p53 tumour suppressor is regulated mainly by Mdm2, an E3 ubiquitin ligase that promotes the ubiquitylation and proteasome-mediated degradation of p53. Many agents that induce p53 are inhibitors of transcription, suggesting that the p53 pathway can detect a signal(s) arising from transcriptional malfunction. Mdm2 associates with TAFII250, a component of the general transcription factor TFIID. Inactivation of TAFII250 in ts13 cells, which express a temperature-sensitive mutant of TAFII250, leads to the induction of p53 and cell cycle arrest. In the present study, we show that TAFII250 stimulates the ubiquitylation and degradation of p53 in a manner that is dependent upon Mdm2 and requires its acidic domain. Mechanistically, TAFII250 downregulates Mdm2 auto-ubiquitylation, leading to Mdm2 stabilization, and promotes p53-Mdm2 association through a recently defined second binding site in the acidic domain of Mdm2. These data provide a novel route through which TAFII250 can directly influence p53 levels and are consistent with the idea that the maintenance of p53 turnover is coupled to the integrity of RNA polymerase II transcription.
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PMID:Transcription factor TAFII250 promotes Mdm2-dependent turnover of p53. 1723 21

Mdm2 is an E3 ubiquitin ligase that promotes its own ubiquitination and also ubiquitination of the p53 tumour suppressor. In a bacterial two-hybrid screen, using Mdm2 as bait, we identified an Mdm2-interacting peptide that bears sequence similarity to the deubiquitinating enzyme USP2a. We have established that full-length USP2a associates with Mdm2 in cells where it can deubiquitinate Mdm2 while demonstrating no deubiquitinating activity towards p53. Ectopic expression of USP2a causes accumulation of Mdm2 in a dose-dependent manner and consequently promotes Mdm2-mediated p53 degradation. This differs from the behaviour of HAUSP, which deubiquitinates p53 in addition to Mdm2 and thus protects p53 from Mdm2-mediated degradation. We further demonstrate that suppression of endogenous USP2a destabilises Mdm2 and causes accumulation of p53 protein and activation of p53. Our data identify the deubiquitinating enzyme USP2a as a novel regulator of the p53 pathway that acts through its ability to selectively target Mdm2.
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PMID:The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. 1729 Feb 20

Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. Loss of Mdm2 in mice results in p53-dependent apoptosis and embryonic lethality. This phenotype was rescued by the p53(515C) allele, which encodes an apoptosis-deficient p53R172P protein. However, these mice died within 2 weeks of birth, due to a severe impairment of progenitor cell expansion during postnatal haematopoiesis and cerebellar development, leading to p53-dependent cell cycle arrest. Loss of Mdm2 led to phosphorylation of the p53R172P protein, p53R172P stability and activation of the cell cycle inhibitor p21 in proliferating cells, but not in differentiated cells, in multiple tissue compartments. Proliferating cells of epithelial origin were not affected. The haematopoietic and neural defects were alleviated in mice lacking Mdm2 and containing one p53(515C) and one p53-null allele, but spermatogenesis was arrested. These findings establish a crucial role for the p53-Mdm2 network in regulating proliferation and progenitor expansion in many cell lineages and have important implications for the use of drugs that aim to disrupt the p53-Mdm2 interaction.
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PMID:The p53-Mdm2 network in progenitor cell expansion during mouse postnatal development. 1797 40

NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family. NUMB is also an endocytic protein, and the NOTCH-NUMB counteraction has been linked to this function. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH. Thus, in these cancers, a single event-loss of NUMB expression-determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry.
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PMID:NUMB controls p53 tumour suppressor activity. 1817 99

The von Hippel-Lindau (VHL) tumour suppressor protein is important in the E3 ubiquitin ligase ECV (Elongin B/C-CUL2-VHL)-mediated destruction of hypoxia-inducible factor and the promotion of fibronectin (FN) extracellular matrix assembly. Although the precise molecular mechanism controlling the selectivity of VHL function remains unknown, a failure in either process is associated with oncogenic progression. Here, we show that VHL performs its FN-associated function independently of the ECV complex, highlighting the autonomy of these pathways. Furthermore, we show that NEDD8, a ubiquitin-like molecule, acts as a 'molecular switch' in which its covalent conjugation to VHL prohibits the engagement of the scaffold component CUL2 and, concomitantly, activates the association with FN. These findings provide the first mechanistic step in defining the functional selectivity of VHL and explain a previously unrecognized function of NEDD8.
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PMID:NEDD8 acts as a 'molecular switch' defining the functional selectivity of VHL. 1832 57


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