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)

Our understanding of the molecular pathology underlying the development and progression of ductal pancreatic cancer has been revolutionised during the last 5 years due to the spectacular development of novel molecular biological techniques. In the present article, we describe key molecular alterations of sporadic and inherited ductal pancreatic cancer. Overexpression of growth factors and growth factor receptors are present in a significant proportion of this tumour type. Mutation of the K-ras oncogene, and disruption of p53 or p16 tumour suppressor gene abrogates the control of the cyclin-dependent kinases (cdk) and retinoblastoma (Rb) gene pathway, causing continuous growth of the pancreatic tumour. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor beta signalling pathway. Lost or decreased expression of retinoid receptors and failure of telomerase activity may play a role in pancreatic carcinogenesis. Tumour-associated proteinases, matrix metalloproteinases and plasminogen activators are reported to be involved in pancreatic cancer invasion and metastasis. Furthermore, the cytogenetic changes in this cancer are summarised. This molecular pattern distinguishes pancreatic cancer from other epithelial tumours and represents a promising basis for the development of diagnostic and other clinical applications.
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PMID:Molecular pattern of ductal pancreatic cancer. 964 82

The retinoblastoma (RB) tumour suppressor protein negatively regulates cell proliferation by modulating transcription of growth-regulatory genes. Recruitment of Rb to promoters, by association with E2F complex or by fusion with heterologous DNA-binding domains, demonstrated that Rb represses directly transcription. Recent studies also suggest that the RB protein is able to repress gene transcription mediated by the RNA polymerase I and III. Since the TATA-binding protein (TBP) is an important component for transcription mediated by all three RNA polymerases, we have analysed the functional interaction between Rb and TBP in vivo in the context of RNA pol II-driven transcription. We demonstrated that in mammalian cells Rb tethered to promoter represses TBP-mediated activation in vivo, and Rb-mediated repression is reversed in the presence of the inhibition of histone deacetylase activity by trichostatin A (TSA).
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PMID:Retinoblastoma protein tethered to promoter DNA represses TBP-mediated transcription. 967 Dec 33

The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the alpha transcript, p16(INK4a), is a recognized tumour suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G1 and G2/M. As a consequence, p14(ARF)-induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14(ARF) acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14(ARF) expression and there is an inverse correlation between p14(ARF) expression and p53 function in human tumour cell lines. However, p14(ARF) expression is not involved in the response to DNA damage. These results place p14(ARF) in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.
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PMID:The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. 972 36

The SV40 large T antigen (T antigen) is a potent viral oncogene capable of inducing tumours in test animals and transforming cells in culture. T antigen possesses multiple transforming functions that act in a cell-type dependent manner. One of these transforming functions requires a physical association between T antigen and the cellular tumour suppressor p53, while another requires T antigen binding to the retinoblastoma family of tumour suppressors. A third transforming function, <<Activity X>>, maps to the amino terminus of large T antigen, sequences also present in small t antigen. Our recent studies have shown that Activity X: (i) is a J-domain and that T antigen possesses the biochemical properties of a DnaJ molecular chaperone; (ii) must act in cis with the T antigen Rb-family binding motif to transform; and, (iii) must act in cis with some factor through its carboxy terminal half of T antigen, possibly p53, to transform.
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PMID:Molecular chaperone function of the SV40 large T antigen. 977 52

Progression of cells into S phase is controlled by the retinoblastoma protein (pRB) and relies on the functional inactivation of this tumour suppressor in late G1 via protein phosphorylation. We provide evidence here that, besides controlling entry of cells into S phase, pRB can operate to inhibit S phase completion. Differential arrays of phosphorylation appear to regulate these different events, suggesting that cycle progression at these two stages of the cell cycle may be achieved via activation of distinct downstream pRB effector pathways. In agreement with this hypothesis, pRB's ability to prevent S phase entry, but not its ability to inhibit S phase completion, correlates with repression of E2F-regulated promoters. Furthermore, ectopic expression of E2F or the E2F-regulated cyclin E gene promote S phase entry in cells expressing phosphorylation-defective pRB but neither is sufficient to trigger completion of S phase. Our findings raise the possibility that pRB, in addition to its well-established role in controlling a checkpoint in late G1, could be involved in the control of a further checkpoint operating during S phase and that implementation of this checkpoint relies on an as yet unidentified pRB effector distinct from E2F.
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PMID:pRB phosphorylation mutants reveal role of pRB in regulating S phase completion by a mechanism independent of E2F. 981 49

Cyclin dependent kinase inhibitor 2/multiple tumour suppressor gene 1 (CDKN2/MTS1) and retinoblastoma (Rb) tumour suppressor genes play important roles in the regulation of the cell cycle. The protein products of these genes p16INK4 (p16) and pRb, respectively, like p53 protein inhibit progression from G1 to S phase. p16 exerts its function through inhibition of CDK4-mediated phosphorylation of pRb. The pRb/p16 pathway is a critical target for molecular aberration at the G1-S checkpoint in a wide range of primary human tumours. The expression of p16 and pRb proteins was analyzed by immunohistochemistry in 35 cases of oral squamous cell carcinomas (SCCs), 22 cases of premalignant oral lesions and 30 normal oral tissues. Lack of pRb expression was observed in 23/35 (66%) oral SCCs and 14/22 (64%) premalignant lesions. Lack of p16 expression was observed in 22/35 (63%) oral SCCs and 13/22 (59%) premalignant lesions. Weak p16 and pRb immunoreactivities were observed in normal oral mucosal epithelium. The status of p16 and pRb was correlated with clinicopathological characteristics of the patients. Alteration in p16 expression showed significant correlation with tumour staging and progression (P = 0.024). Alteration in pRb/p16 expression correlated with heavy consumption of betel and tobacco. Our results suggest that alterations in the p16/pRb pathway are early events in oral tumorigenesis and may be involved in the development of betel- and tobacco-related oral malignancies.
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PMID:pRb and p16 protein alterations in human oral tumorigenesis. 986 48

p16MTS1/CDKN1 and the retinoblastoma protein Rb are both involved in negative regulation of G1/S progression in the mammalian cell cycle. Inactivation of one of these tumour suppressor genes is involved in many malignant tumours, and in some studies a negative correlation of p16 and Rb expression has been found. In order to study this interaction in endometrial carcinogenesis, we investigated 36 endometrial carcinomas, 11 cases of hyperplasia, 23 normal endometrial samples, and two uterine carcinoma cell lines by immunohistochemistry or RT-PCR. Rb was expressed in normal endometrial epithelium, hyperplasia, cell lines, and most carcinomas; negative immunostaining was only detected in 1 of 36 tumours. In contrast, p16 expression was weak in normal endometrium and increased in most cases of hyperplasia, but negative or minimally positive in 74% of the carcinomas and the Hec1B adenocarcinoma cell line, and there was no significant association with Rb immunostaining. Strikingly high p16 expression was found in foci of squamous metaplasia within hyperplastic or carcinomatous tissue. Deletion and mutation analysis of the p16 gene was performed in DNA from microdissected tumour samples and cell lines. No p16 deletion was found, and mutations were detected in only one tumour sample and Skut1B uterine mixed mesodermal tumour cells. Our data indicate that in spite of low or absent p16 expression, genetic alterations of the p16 and Rb tumour suppressor genes are rare in endometrial carcinogenesis.
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PMID:P16/MTS1 and pRB expression in endometrial carcinomas. 1007 Dec 31

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases, whereas p19ARF targets MDM2, a p53 inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways. To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-three (62%) tumours had alterations of one or more p53 pathway components (p53, p19ARF and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2. The lack of correlation between these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways.
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PMID:Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. 1008 36

A wide array of proto-oncogenes and tumour suppressor genes are involved in the prevention of cancer. Each form of cancer requires mutations in a characteristic group of genes, but no single group controls all cancers. This lack of generality shows that the control of cancer is not an ancient, fixed property of cells. By contrast, it supports a dynamic evolutionary model, whereby genetic controls over unregulated cell growth are recruited independently through evolutionary time in different tissues within different taxa. The complexity of this genetic control can be predicted from a population genetic model of lineage selection driven by the detrimental fitness effects of cancer. Cancer occurs because the genetic control of cell growth is vulnerable to somatic mutations (or 'hits'), particularly in large, continuously dividing tissues. Thus, compared to small rodents, humans must have evolved more complex genetic controls over cell growth in at least some of their tissues because of their greater size and longevity; an expectation relevant to the application of mouse data to humans. Similarly, the 'two-hit' model so successfully applied to retinoblastoma, which originates in a small embryonic tissue, is unlikely to be generally applicable to other human cancers; instead, more complex scenarios are expected to dominate, with complexity depending upon a tissue's size and its pattern of proliferation.
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PMID:Lineage selection and the evolution of multistage carcinogenesis. 1018 13

Apoptosis in human monocytic THP.1 tumour cells, induced by diverse stimuli, was accompanied by proteolytic cleavage of the adenomatous polyposis coli gene product (APC) and by sequential cleavage of the retinoblastoma susceptibility gene product (Rb). Cleavage of poly(ADP-ribose) polymerase (PARP), APC and the initial cleavage of Rb at the carboxy terminal region all occurred at a similar time, early in the apoptotic process. Subsequently, Rb underwent a secondary cleavage to 43 kDa and 30 kDa protein fragments. Two caspase inhibitors, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK) and acetyl-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD.CMK), had markedly different effects on the induction of apoptosis. Z-VAD.FMK inhibited the primary and secondary cleavage of Rb, cleavage of APC and PARP, and apoptosis assessed by flow cytometry. In marked contrast, YVAD.CMK inhibited cleavage of APC and the secondary cleavage of Rb to the 43 kDa and 30 kDa protein fragments but did not inhibit the primary carboxy terminal cleavage of Rb, PARP proteolysis or apoptosis assessed by flow cytometry. These results suggest that different caspases are responsible for the cleavage of different substrates at different stages during the apoptotic process and that a caspase may either cleave APC directly or may be involved in the pathway leading to APC proteolysis. This is the first report suggesting that a cytoplasmic tumour suppressor gene (APC) may be cleaved by a caspase during apoptosis.
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PMID:The adenomatous polyposis coli protein and retinoblastoma protein are cleaved early in apoptosis and are potential substrates for caspases. 1020 Apr 66


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