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

Cyclin-dependent kinase inhibitors (cdkis), such as p21, are believed to control proliferation through an ability to function as stoichiometric antagonists of cyclin-dependent kinases (cdks). The p21 gene is a direct transcriptional target for the p53 protein, and its activation is likely to be important in effecting the p53 response. It is widely accepted that p21 can influence cell cycle progression by controlling the activity of cdks that act on the retinoblastoma tumour suppressor protein (pRb) which, in a hypophosphorylated state, associates with E2F transcription factors to prevent the activation of genes required for progression into S phase. Phosphorylation of pRb by G1 cdk complexes releases E2F and thereby enables progress through the cell cycle. Here, we describe results which suggest a p21-dependent mechanism that facilitates the regulation of E2F through a pathway that is independent of the cdk control of pRb activity. As p21 can associate with E2F subunits, it is possible that these effects are exerted through a complex with E2F. Furthermore, we find that p21 can regulate transcription in vitro. The results suggest that p21 may control E2F activity through a pathway that acts independently of pRb.
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PMID:Control of E2F activity by p21Waf1/Cip1. 1049 92

Women heterozygous for mutations in the breast-cancer susceptibility genes BRCA1 and BRCA2 have a highly elevated risk of developing breast cancer [1]. BRCA1 and BRCA2 encode large proteins with no sequence similarity to one another. Although involvement in DNA repair and transcription has been suggested, it is still not understood how loss of function of these genes leads to breast cancer [2]. Embryonic fibroblasts (MEFs) derived from mice homozygous for a hypomorphic mutation (Brca2(Tr2014)) within the 3' region of exon 11 in Brca2 [3], or a similar mutation (Brca2(Tr)) [4], proliferate poorly in culture and overexpress the tumour suppressor p53 and the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). These MEFs have intact p53-dependent DNA damage G(1)-S [3] [4] and G(2)-M checkpoints [4], but are impaired in DNA double-strand break repair [3] and develop chromosome aberrations [4]. Here, we report that Brca2(Tr2014/Tr2014) MEFs frequently develop micronuclei. These abnormal DNA-containing bodies were formed through both loss of acentric chromosome fragments and by chromosome missegregation, which resulted in aneuploidy. Absence of Brca2 also led to centrosome amplification, which we found associated with the formation of micronuclei. These data suggest a potential mechanism whereby loss of BRCA2 may, within subclones, drive the loss of cell-cycle regulation genes, enabling proliferation and tumourigenesis.
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PMID:Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. 1053 Oct 7

Representational difference analysis (RDA) of a human glioblastoma xenograft resulted in the isolation of five tumour-associated homozygously deleted DNA fragments, all originating from chromosome 9, region p21. Subsequent analysis of a series of ten glioblastomas using the newly isolated RDA fragments in conjunction with a series of known 9p21 DNA markers revealed homozygous deletions in nine of the ten (90 per cent) tumours. These deletions encompass the p15/p16 complex and two additional putative tumour suppressor loci. The RDA fragments correspond to the latter two loci. Taken together, these results suggest the involvement of multiple tumour suppressor genes from the 9p21 region in glioblastoma tumourigenesis. The novel RDA fragments will be instrumental in the isolation of the relevant genes.
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PMID:Isolation and characterization of glioblastoma-associated homozygously deleted DNA fragments from chromosomal region 9p21 suggests involvement of multiple tumour suppressor genes. 1054 3

This paper describes the generation and characterization of a monoclonal antibody specific for two members of the AP-2 family of transcription factors, AP-2alpha and AP-2beta, and its subsequent application to archival primary breast tumour material. Nuclear localization of AP-2 was found in all expressing cases, but in general levels of immunostaining were low, with only 17 per cent of the 86 tumours examined showing very high expression levels. Nevertheless, data analysis of the whole patient series allowed the identification of significant relationships between levels of AP-2 and other important breast markers. Thus, expression of AP-2alpha/beta was found to correlate significantly with expression of both ER ( p=0.036*) and the universal cell-cycle inhibitor p21(cip) ( p=0.03*), but was inversely related to levels of the proto-oncogene ErbB2 ( p=0.008*). AP-2-positive tumours also showed a low rate of proliferation, with significantly reduced mitotic count and a lower tumour grade. There was no significant relationship with clinical parameters, but samples with adjacent normal tissue indicated that loss of the AP-2 marker was associated with disease progression from normal breast through to invasive disease. This was confirmed by examining separate series of pure normal and pure DCIS samples, both of which expressed significantly higher levels of AP-2 ( p=0.0001* in each case) than the invasive tumours. Overall, these findings implicate AP-2alpha/beta as having a role akin to that of a tumour suppressor in breast cancer.
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PMID:Immunohistochemical analysis reveals a tumour suppressor-like role for the transcription factor AP-2 in invasive breast cancer. 1062 51

The coding regions of tumour suppressor and cell cycle regulatory genes p21 WAF1 and p27 Kip1 were investigated in 101 feline tumours of various types. No damaging mutations were present in the analysed areas of the genes.
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PMID:Absence of p21 WAF1 and p27 kip1 gene mutations in various feline tumours. 1072 97

The prognostic value of the expression of the cyclin-dependent kinase inhibitor p21 and the p53 tumour suppressor gene was examined using immunohistochemistry in 60 patients with laryngeal cancer. Multivariate analysis using Cox's proportional hazard method, showed that p21 expression (P = 0.02) and advanced T stage (P = 0.003) significantly predicted survival. It was concluded that p21 expression may be a useful prognostic indicator in laryngeal cancer.
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PMID:Expression of cyclin-dependent kinase inhibitor p21(WAF1) and p53 tumour suppressor gene in laryngeal cancer. 1076 33

The aim was to investigate the combined immunoexpression of p53, p21, bcl-2, bax, Rb and Ki67 proteins in Hodgkin's lymphomas (HL) and correlate expression patterns with the histotype and the Epstein-Barr Virus (EBV) status. Paraffin-sections from 56 cases of HL (18 nodular sclerosis and 38 mixed cellularity) and from ten "reactive" lymph nodes were investigated. P53, p21, bcl-2, bax, Rb and Ki67 proteins were detected in Hodgkin and Reed-Sternberg (HRS) cells in 35/56, 56/56, 24/56, 23/56, 56/56 and 56/56 cases of HL, respectively. No correlation was found between the expression of each protein and the EBV status or the histotype of HL. Comparison between p53 and p21 staining revealed two patterns: a) p53+/p21+ (35 cases); and b) p53-/p21+ (21 cases). The pattern p53+/p21+ suggests wild type p53 protein able to induce the expression of p21 while the p53-/p21+ pattern suggests p53-independent p21 expression. These results are consistent with the interpretation that inactivating p53 gene mutations may be rare in HL. Comparison between bcl-2 and bax staining showed a statistically significant relationship (p<0.001) for coexpression (19 cases) or absence of expression of both proteins (28 cases) in HRS cells. In contrast, bax expression was observed in most lymphoid cells in all "reactive" lymph nodes. Since the proapoptotic bax protein may act as tumour suppressor it is possible that the absence of this protein in HRS cells in a substantial proportion of HL may confer growth advantage and play a role in their pathogenesis. This could suggest bax gene alterations in some HL since in other studies acute lymphoblastic leukaemia cell lines demonstrate bax gene mutations with loss of bax immunoexpression. Another possibility is that reduced bax expression may be due to post transcriptional regulation, as was described in lymphoma cell lines. Comparison between Rb and Ki67 staining disclosed two main deviations from the normal parallel relationship in reactive lymph nodes: a) 2 cases with low Rb and high Ki67 expression possibly reflecting loss of Rb expression due to chromosome loss or to other abnormalities in the structure or the expression of Rb gene; and b) 9 cases with high RB and low Ki67 possible reflecting an attempt of Rb protein in excess to induce cell cycle arrest. Taken together, our findings provide combined immunohistological evidence for deregulated expression of cell-cycle and apoptosis-related proteins, that may play a role in the pathogenesis of HL.
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PMID:Expression of p53, p21/waf1, bcl-2, bax, Rb and Ki67 proteins in Hodgkin's lymphomas. 1080 63

Through a glucocorticoid-responsive promoter, glucocorticoids can regulate the transcription of the human papillomavirus (HPV) E6 and E7 viral genes which target the tumour suppressor proteins p53 and Rb respectively. In C4-1 cells, the glucocorticoid dexamethasone up-regulated HPV E6/E7 mRNA and decreased radiation-induced apoptosis. In contrast, dexamethasone had no effect on apoptosis of cells that either lack the HPV genome (C33-a) or in which HPV E6/E7 transcription is repressed by dexamethasone (SW756). Irradiated C4-1 cells showed increased p53 expression, while dexamethasone treatment prior to irradiation decreased p53 protein expression. In addition, p21 mRNA was regulated by irradiation and dexamethasone in accordance with the observed changes in p53. Overall, glucocorticoids decreased radiation-induced apoptosis in cervical carcinoma cells which exhibit increased HPV E6/E7 transcription and decreased p53 expression. Therefore, in HPV-infected cervical epithelial cells, p53-dependent apoptosis appears to depend upon the levels of HPV E6/E7 mRNA.
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PMID:Inhibition of radiation-induced apoptosis by dexamethasone in cervical carcinoma cell lines depends upon increased HPV E6/E7. 1081 8

Using an improved system for the functional identification of active antisense fragments, we have isolated antisense fragments which inactivate the p53 tumour suppressor gene. These antisense fragments map in two small regions between nt 350 and 700 and nt 800 and 950 of the coding sequence. These antisense fragments appear to act by inhibition of p53 mRNA translation both in vivo and in vitro. Expression of these antisense fragments overcame the p53-induced growth arrest in a cell line which expresses a thermolabile mutant of p53 and extended the in vitro lifespan of primary mouse embryonic fibroblasts. Continued expression of the p53 antisense fragment contributed to immortalisation of primary mouse fibroblasts. Subsequent elimination of the antisense fragment in these immortalised cells led to restoration of p53 expression and growth arrest, indicating that immortal cells continuously require inactivation of p53. Expression of MDM2 or SV40 large T antigen, but not E7 nor oncogenic ras, overcomes the arrest induced by restoration of p53 expression. Functional inactivation of both p21 and bax (by overexpression of Bcl2), but not either alone, allowed some bypass of p53-induced growth arrest, indicating that multiple transcriptional targets of p53 may mediate its antiproliferative action. The ability to conditionally inactivate and subsequently restore normal gene function may be extremely valuable for genetic analysis of genes for which loss-of-function is involved in specific phenotypes.
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PMID:Loss-of-function genetics in mammalian cells: the p53 tumor suppressor model. 1087 44

An initiating role for RAS oncogene mutation in several epithelial cancers is supported by its high incidence in early-stage tumors and its ability to induce proliferation in the corresponding normal cells in vitro. Using retroviral transduction of thyroid epithelial cells as a model we ask here: (i) how mutant RAS can induce long-term proliferation in an epithelial cell in contrast to the premature senescence observed in fibroblasts; and (ii) what is the "clock" which eventually triggers spontaneous growth arrest even in epithelial clones generated by mutant RAS. The early response to RAS activation in thyroid epithelial cells showed two features not seen in fibroblasts: (i) a marked decrease in expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1) and (ii) the absence of any induction of p21(waf1). When proliferation eventually ceased (after up to 20 population doublings) this occurred despite undiminished expression of mutant RAS and was tightly correlated with a return to the initial high level of p27(kip1) expression, together with the de novo appearance of p16(ink4a). Importantly, neither the CDKI changes nor the proliferative life span of RAS-induced epithelial clones was altered by induction of telomerase activity through forced expression of the catalytic subunit, hTERT, at levels sufficient to immortalize human fibroblasts. These data provide a basis for cell-type differences in sensitivity to RAS-induced proliferation which may explain the corresponding tumor-type specificity of RAS mutation. They also show for the first time in a primary human cell model that a telomere-independent mechanism can limit not only physiological but also oncogene-driven proliferation, pointing therefore to a tumour suppressor mechanism additional, or alternative, to the telomere clock.
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PMID:Evidence for a telomere-independent "clock" limiting RAS oncogene-driven proliferation of human thyroid epithelial cells. 1089 5


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