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)

Haploinsufficiency of the human 17p13.3 region is associated with 35% to 50% of medulloblastomas, indicating the presence of one or more tumour suppressor genes which have not yet been identified. Of 119 genes residing in this region, seven genes--14-3-3epsilon (YWHAE), HIC-1, ROX/MNT (a helix-loop-helix transcription factor and member of the MYC/MAX superfamily), KIAA0399, UBE2G1 (ubiquitin ligase), ALOX15, and MINK--encode proteins with potential links to cancer. We investigated these genes and found significant levels of expression of ROX/MNT in adult human cerebellum, and in embryonic and postnatal mouse cerebellum. Six of 14 medulloblastomas showed a reduction of ROX/MNT expression, accompanied by a reduction of both UBE2G1 and 14-3-3epsilon in three tumours and a reduction of UBE2G1 in one tumour. Moreover, the relative expression of MYC to ROX/MNT was increased in 4 of the 14 medulloblastomas. Collectively, these data suggest that ROX/MNT should be considered a potential tumour suppressor gene in medulloblastoma.
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PMID:Analysis of transcripts from 17p13.3 in medulloblastoma suggests ROX/MNT as a potential tumour suppressor gene. 1551 29

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. Here we identify the mouse Fbxw7 gene as a p53-dependent tumour suppressor gene by using a mammalian genetic screen for p53-dependent genes involved in tumorigenesis. Radiation-induced lymphomas from p53+/- mice, but not those from p53-/- mice, show frequent loss of heterozygosity and a 10% mutation rate of the Fbxw7 gene. Fbxw7+/- mice have greater susceptibility to radiation-induced tumorigenesis, but most tumours retain and express the wild-type allele, indicating that Fbxw7 is a haploinsufficient tumour suppressor gene. Loss of Fbxw7 alters the spectrum of tumours that develop in p53 deficient mice to include a range of tumours in epithelial tissues such as the lung, liver and ovary. Mouse embryo fibroblasts from Fbxw7-deficient mice, or wild-type mouse cells expressing Fbxw7 small interfering RNA, have higher levels of Aurora-A kinase, c-Jun and Notch4, but not of cyclin E. We propose that p53-dependent loss of Fbxw7 leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.
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PMID:Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. 1559 18

The tumour suppressor ARF (alternative reading frame) is encoded by the INK4a (inhibitor of cyclin-dependent kinase 4)/ARF locus, which is frequently altered in human tumours. ARF binds MDM2 (murine double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53. Recently, ARF has been found to associate with other proteins, but, to date, little is known about ARF-associated proteins that are implicated in post-translational regulation of ARF activity. Using a yeast two-hybrid screen, we have identified a novel protein, LZAP (LXXLL/leucine-zipper-containing ARF-binding protein), that interacts with endogenous ARF in mammalian cells. In the present study, we show that LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity towards p53, but simultaneously co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional activity. Expression of LZAP, in addition to ARF, increased the percentage of cells in the G1 phase of the cell cycle. Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle arrest in the absence of ARF. Taken together, our data suggest that LZAP can regulate ARF biochemical and biological activity. Additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF.
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PMID:A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. 1617 22

The Murine double-minute clone 2 (Mdm2) onco-protein is the principal regulator of the tumour suppressor, p53. Mdm2 acts as an E3-type ubiquitin ligase that mediates the ubiquitylation and turnover of p53 under normal, unstressed circumstances. In response to cellular stress, such as DNA damage, the Mdm2-p53 interaction is disrupted. Part of the mechanism of uncoupling p53 from Mdm2-mediated degradation involves hypo-phosphorylation of a cluster of phosphorylated serine residues in the central acidic domain of Mdm2. Here, we show that two of the residues within this domain that are phosphorylated in vivo, Ser-260 and Ser-269, are phosphorylated by CK2 in vitro. Treatment of cells with the CK2 inhibitor, 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), leads to the induction of p53 and downstream targets of p53 including Mdm2 itself and p21. These data are consistent with the idea that CK2-mediated phosphorylation of Mdm2 may regulate Mdm2-mediated p53 turnover.
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PMID:Phosphorylation of the acidic domain of Mdm2 by protein kinase CK2. 1633 31

hCDC4, a ubiquitin ligase, plays a role in the control of cell cycle and chromosome stability. The hCDC4 gene is considered a tumour suppressor gene and is mutated in several human neoplasias, including colorectal and endometrial tumours. Data on the hCDC4 mutation in gastric cancer is, however, lacking. This study explored the possibility that hCDC4 mutation is involved in the development of gastric cancer. The hCDC4 gene in 162 gastric adenocarcinoma tissues was analysed for somatic mutations using a polymerase chain reaction-single strand conformation polymorphism assay. Overall, six hCDC4 mutations were found (3.7%), comprising four missense, one frameshift deletion and one nonsense mutation(s). It is notable that the hCDC4 mutations were found in early as well as in advanced gastric carcinomas. These data indicate that hCDC4 mutation occasionally occurs in gastric carcinomas and suggest that it might play a role in the development of some gastric carcinomas.
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PMID:Mutational analysis of the hCDC4 gene in gastric carcinomas. 1682 48

The tumour suppressor p53 induces apoptosis or cell-cycle arrest in response to genotoxic and other stresses. In unstressed cells, the anti-proliferative effects of p53 are restrained by mouse double minute 2 (Mdm2), a ubiquitin ligase (E3) that promotes p53 ubiquitination and degradation. Mdm2 also mediates its own degradation through auto-ubiquitination. It is unclear how the cis- and trans-E3 activities of Mdm2, which have opposing effects on cell fate, are differentially regulated. Here, we show that death domain-associated protein (Daxx) is required for Mdm2 stability. Downregulation of Daxx decreases Mdm2 levels, whereas overexpression of Daxx strongly stabilizes Mdm2. Daxx simultaneously binds to Mdm2 and the deubiquitinase Hausp, and it mediates the stabilizing effect of Hausp on Mdm2. In addition, Daxx enhances the intrinsic E3 activity of Mdm2 towards p53. On DNA damage, Daxx dissociates from Mdm2, which correlates with Mdm2 self-degradation. These findings reveal that Daxx modulates the function of Mdm2 at multiple levels and suggest that the disruption of the Mdm2-Daxx interaction may be important for p53 activation in response to DNA damage.
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PMID:Critical role for Daxx in regulating Mdm2. 1688 Aug 12

The p53 tumour suppressor has a key role in the control of cell growth and differentiation, and in the maintenance of genome integrity. p53 is kept labile under normal conditions, but in response to stresses, such as DNA damage, it accumulates in the nucleus for induction of cell-cycle arrest, DNA repair or apoptosis. Mdm2 is an ubiquitin ligase that promotes p53 ubiquitination and degradation. Mdm2 is also self-ubiquitinated and degraded. Here, we identified a novel cascade for the increase in p53 level in response to DNA damage. A new SUMO-specific protease, SUSP4, removed SUMO-1 from Mdm2 and this desumoylation led to promotion of Mdm2 self-ubiquitination, resulting in p53 stabilization. Moreover, SUSP4 competed with p53 for binding to Mdm2, also resulting in p53 stabilization. Overexpression of SUSP4 inhibited cell growth, whereas knockdown of susp4 by RNA interference (RNAi) promoted of cell growth. UV damage induced SUSP4 expression, leading to an increase in p53 levels in parallel with a decrease in Mdm2 levels. These findings establish a new mechanism for the elevation of cellular p53 levels in response to UV damage.
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PMID:SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination. 1708 74

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.
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PMID:14-3-3sigma controls mitotic translation to facilitate cytokinesis. 1736 Nov 71

The E6 proteins of high-risk genital human papillomaviruses (HPV), such as HPV types 16 and 18, possess a conserved C-terminal PDZ-binding motif, which mediates interaction with some cellular PDZ domain proteins. The binding of E6 usually results in their ubiquitin-mediated degradation. The ability of E6 to bind to PDZ domain proteins correlates with the oncogenic potential. Using a yeast two-hybrid system, GST pull-down experiments and coimmunoprecipitations, we identified the protein tyrosine phosphatase H1 (PTPH1/PTPN3) as a novel target of the PDZ-binding motif of E6 of HPV16 and 18. PTPH1 has been suggested to function as tumour suppressor protein, since mutational analysis revealed somatic mutations in PTPH1 in a minor fraction of various human tumours. We show here that HPV16 E6 accelerated the proteasome-mediated degradation of PTPH1, which required the binding of E6 to the cellular ubiquitin ligase E6-AP and to PTPH1. The endogenous levels of PTPH1 were particularly low in HPV-positive cervical carcinoma cell lines. The reintroduction of the E2 protein into the HPV16-positive cervical carcinoma cell line SiHa, known to lead to a sharp repression of E6 expression and to induce growth suppression, resulted in an increase of the amount of PTPH1. Our data suggest that reducing the level of PTPH1 may contribute to the oncogenic activity of high-risk genital E6 proteins.
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PMID:Protein tyrosine phosphatase H1 is a target of the E6 oncoprotein of high-risk genital human papillomaviruses. 1794 17

FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCF(FBW7) degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.
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PMID:FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. 1809 23


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