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)

Bax is a pro-apoptotic member of the Bcl-2 family of genes which regulate programmed cell death. The Bax protein shares highly conserved domains with Bcl-2, some of which are required for the formation of Bax-Bcl-2 heterodimers. Bax expression is elevated in certain tissues after apoptotic stimuli and can be directly regulated by p53. Bax -/- mice have increased numbers of lymphoid cells and bax -/- neurons survive in culture following nerve growth factor deprivation. Bax can accelerate cell cycle entry in T-cells and has recently been shown to have a tumour suppressor function as well as carrying mutations in certain cancers. Bax can form ion-conducting channels in planar lipid bilayers which may be the biochemical mechanism through which it exerts its multiple effects. Pharmacological manipulation of Bax has implications for many diseases involving apoptosis such as cancer or neurodegenerative disorders.
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PMID:Bax. The pro-apoptotic Bcl-2 family member, Bax. 969 20

The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous c-abl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative fibroblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative fibroblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that c-abl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000).
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PMID:c-abl is involved in the association of p53 and trk A. 1087 55

trk A tyrosine kinase (the high affinity receptor for nerve growth factor) binds to the p53 tumour suppressor protein in vitro and in vivo. Our aim was to determine which regions of p53 are involved in trk A association. In vitro binding experiments using baculovirus expressed trk A and in vitro transcribed and translated C-terminus p53 deletion mutants show amino acids 327-338 critical for association. Also, analysis with mutants at the N-terminus, conserved regions II, III, IV and V or amino acid positions 173, 175, 181, 248 and 249 (which are amino acids frequently mutated in a variety of neoplasms and transformed cell lines), show that these sites are not involved in trk A binding. Importantly, similar results are obtained after immunoprecipitation of lysates from p53 negative fibroblasts expressing trk A and the above p53 mutant proteins. These data suggest that the amino-terminus of the oligomerisation domain of p53 is involved in p53/trk A association.
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PMID:Analysis of trk A and p53 association. 1137 56

NF-kappaB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis. In most cells, these factors are kept inactive in the cytoplasm through association with IkappaB inhibitors. After stimulation by various reagents, IkappaB is phosphorylated by the IkappaB kinase (IKK) complex and degraded by the proteasome, allowing NF-kappaB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK. CYLD also interacts directly with tumour-necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), an adaptor molecule involved in signalling by members of the family of TNF/nerve growth factor receptors. CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology.
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PMID:The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. 1291 71

Proteomic technology has recently emerged as a powerful tool for detecting both qualitative and quantitative changes of proteins that occur upon activation of complex signaling pathways. In the present study, comparison of the protein profile of platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and nerve growth factor (NGF)-stimulated and unstimulated cells with two-dimensional electrophoresis followed by mass spectrometric analysis led to the identification of a number of proteins, several of which had not been previously shown to be regulated by receptor-tyrosine kinases. Using subcellular fractionation, our approach was able to identify not only changes due to altered gene transcription, but also due to intracellular protein translocation or modification. One of the proteins that was identified among other PDGF-regulated molecules was prohibitin, a potential tumour suppressor previously implicated in cell cycle regulation and protection of mitochondrial proteins from degradation. Further analysis confirmed that mitochondria-associated prohibitin translocates to an insoluble perinuclear compartment. This study demonstrates the utility of proteomic strategies in identifying potential growth factor-regulated effectors.
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PMID:Identification of growth factor-regulated proteins using 2D electrophoresis and mass spectrometry. 1624 14

Malignant rhabdoid tumours (MRT) are highly aggressive cancers of early childhood that arise in different organs or tissues. The unifying criterion for these tumours is the presence of inactivating mutations of the hSNF5/INI1 tumour suppressor gene which encodes a core subunit of the chromatin remodelling SWI/SNF complex. Using a variety of markers we analysed the phenotypic traits of MON and DEV cell lines derived respectively from an undifferentiated abdominal MRT and from a brain MRT. DEV cells express spontaneously a wide range of neural and glial markers. It can be induced to differentiate into the neural lineage following hSNF5/INI1 expression with appearance of neurite processes, strong increase of neural markers and decrease of glial markers. A less pronounced neural differentiation is also observed with MON cells, which possess more primitive polyphenotypic features with positivity for markers from the three embryonic layers. Finally, we show that the neural differentiation of rat PC12 cells in the presence of nerve growth factor (NGF) is strongly impaired when hSNF5/INI1 expression is inhibited by RNA interference. Altogether these results indicate that hSNF5/INI1 is an essential subunit for SWI/SNF-dependant induction of neural differentiation programs. Further experiments should enable documentation of whether it provides instructive or permissive signals for differentiation.
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PMID:The tumour suppressor hSNF5/INI1 controls the differentiation potential of malignant rhabdoid cells. 1690 31

The nerve growth factor (NGF) receptor, trkA, the tumour suppressor p53 and the phosphatase SHP-1 are critical in cell proliferation and differentiation. SHP-1 is a trkA phosphatase that dephosphorylates trkA at tyrosines (Y) 674 and 675. p53 can induce trkA activation and tyrosine phosphorylation in the absence of NGF stimulation. In breast cancer tumours trkA expression is associated with increased patient survival. TrkA protein expression is higher in breast-cancer cell lines than in normal breast epithelia. In cell lines (but not in normal breast epithelia) trkA is functional and can be NGF-stimulated to promote cell proliferation. This study investigates the functional relationship between trkA, p53 and SHP-1 in breast-cancer, and reveals that in wild-type (wt) trkA expressing breast-cancer cells both endogenous wtp53, activated by therapeutic agents, and transfected wtp53 repress expression of SHP-1 through the proximal CCAAT sequence of the SHP-1-P1-promoter and the transcription factor NF-Y. In these cells trkA-Y674/Y675 phosphorylation is detected when SHP-1 protein levels decrease in a wtp53-dependent manner. Proliferation and cell-cycle assays, with cells expressing endogenous or transfected wt-trkA and a temperature-sensitive p53 grown at 32 degrees C (when p53 is in the wt configuration), show suppressed cell proliferation. Suppression is not detected when grown at 37 degrees C (when p53 is in the mutant configuration). A release from suppression is observed when these cells are transiently transfected with wt-SHP-1 and grown at 32 degrees C. Suppression is also detected when, as control, wt-trkA-expressing cells are transiently transfected with SHP-1-siRNA, but not when a dominant-negative (DN) mutant trkA is used to abolish wt-trkA activity. Importantly, suppression is not seen with control trkA-negative breast-cancer cells (expressing wtp53, wt-SHP-1 and undetectable trkA), transfected with Y674F/Y675F mutant-trkA. BrdU-incorporation experiments reveal lack of incorporation in cells expressing wt-trkA and wtp53, or wt-trkA and SHP-1-siRNA. However, BrdU is incorporated in the presence of Y674F/Y675F mutant trkA or DN mutant trkA. These results indicate that p53 repression of SHP-1 expression leads to trkA-Y674/Y675 phosphorylation and trkA-dependent suppression of breast-cancer cell proliferation. These data provide an explanation as to why high trkA levels are associated with favourable prognosis.
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PMID:Repression of SHP-1 expression by p53 leads to trkA tyrosine phosphorylation and suppression of breast cancer cell proliferation. 1974 91

Multiple cancer signalling networks take part in regulatory crosstalks with the Hippo tumour suppressor pathway through the transcriptional cofactor Yes-associated protein (YAP). Nevertheless, how YAP is controlled by pathway crosstalks in tumourigenesis remains poorly understood. Here, we performed a targeted kinase inhibitor screen in human cancer cells to identify novel Hippo pathway regulators. Notably, we identified the nerve growth factor (NGF) receptor tyrosine kinase (NTRK1), a molecule not previously associated with Hippo signalling. NTRK1 inhibition decreased YAP-driven transcription, cancer cell proliferation and migration. Furthermore, using a complementary functional genomics approach and mouse xenograft models, we show that NTRK1 regulates YAP oncogenic activity in vivo. Mechanistically, NTRK1 inhibition was found to induce large suppressor kinase 1 (LATS1) phosphorylation and to control YAP subcellular localization. Taken together, these results provide compelling evidence of crosstalks between the NGF-NTRK1 and Hippo cancer pathways.
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PMID:NTRK1 is a positive regulator of YAP oncogenic function. 3054 15