UNIPROT:P43146 - FACTA Search

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Query: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p21(Waf1/Cip1) protein, an inhibitory protein of cellular growth and DNA replication, is induced by the p53 tumour suppressor protein. Any mutations or deletions inactivating the protein may result in unregulated cellular growth. In one aldosterone secreting adrenocortical adenoma, we found a heterozygous deletion of a 111-base-pair (bp) fragment of the p21 cDNA. This deletion resulted in a truncated p21 protein lacking 37 amino acids from codon 65 to 101. The deletion was a somatic mutation, because it was not detected in the DNA of cultured fibroblasts obtained from the same patient. The results suggest that an alteration of the p21 protein may be relevant in inducing an adrenocortical adenoma, a well differentiated and slowly growing benign tumour.
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PMID:A somatic mutation of the p21(Waf1/Cip1) gene in a human adrenocortical adenoma. 906 92

Human diploid fibroblasts lose the capacity to proliferate and enter a state termed replicative senescence after a finite number of cell divisions in culture. When treated with sub-lethal concentrations of H2O2, pre-senescent human fibroblasts enter long-term growth arrest resembling replicative senescence. To understand the molecular basis for the H2O2-induced growth arrest, we determined the cell cycle distribution, levels of p53 tumour suppressor and p21 cyclin-dependent kinase inhibitor proteins, and the status of Rb phosphorylation in H2O2-treated cells. A 2-h pulse of H2O2 arrested the growth of IMR-90 fetal lung fibroblasts for at least 15 days. The arrested cells showed a G1 DNA content. The level of p53 protein increased 2- to 3-fold within 1.5 h after H2O2 exposure but returned to the control level by 48 h. The induction of p53 protein was dose dependent, beginning at 50-75 microM and reaching a maximum at 100-250 microM. The induction of p53 did not appear to correlate with the level of DNA damage as measured by the formation of 8-oxo-2'-deoxyguanosine in DNA. The level of p21 protein increased about 18 h after H2O2 exposure and remained elevated for at least 21 days. During this period, Rb remained underphosphorylated. The induction of p53 by H2O2 was abolished by the iron chelator deferoxamine and the protein synthesis inhibitor cycloheximide. The human papillomavirus protein E6, when introduced into the cells, abolished the induction of p53, reduced the induction of p21 to a minimal level and allowed Rb phosphorylation and entry of the cells into S-phase. The human papillomavirus protein E7 reduced the overall level of Rb and also abolished H2O2-induced G1 arrest. Inactivating G1 arrest by E6, E7 or both did not restore the replicative ability of H2O2-treated cells. Thus H2O2-treated cells show a transient elevation of p53, high level of p21, lack of Rb phosphorylation, G1 arrest and inability to replicate when G1 arrest is inactivated.
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PMID:Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. 957 49

p21waf1/cip1 protein, an inhibitor of cyclin dependent kinases, is a critical downstream target in the p53-specific pathway of growth control, and can also be induced by p53 independent pathways in relation to terminal differentiation. p21waf1 is also a putative tumour suppressor. Hence, we sought to determine whether this protein is abnormally expressed during betel- and tobacco-related oral oncogenesis. The aim was to determine whether a correlation exists between the expression profile of p21 and clinicopathological parameters of the patients, as well as with their p53 status. Immunohistochemical analysis showed that the expression of p21 protein in premalignant lesions was consistently elevated in the superficial, differentiated cells of the epithelium, while overexpression of the p53 tumour suppressor gene was observed in the basal proliferating layers of the epithelium. Our study demonstrated that p21 overexpression is associated with differentiation in proliferating dysplasias and squamous cell carcinomas (SCCs). The expression of p21 and p53 proteins was observed in 11/25 premalignant lesions. In 7 of these 11 cases, a heterogenous pattern of expression of p21 and p53 was observed. Four of these 11 premalignant and 30/51 malignant lesions showed concordant expression of both p21 and p53 proteins. The discordant p21 +/p53- phenotype was observed in 4/25 premalignant lesions and 5/51 oral SCCs. The p21-/p53+ phenotype was observed in 5/25 premalignant lesions and 7/51 oral SCCs. These results suggest that induction of p21 occurs by both p53 dependent and independent mechanisms during oral tumorigenesis.
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PMID:Expression of cyclin dependent kinase inhibitor p21waf1/cip1 in premalignant and malignant oral lesions: relationship with p53 status. 986 40

p73 has been identified as a gene that encodes a protein with significant identity with the tumour suppressor p53. The main structural difference between p73 and p53 is the additional C-terminal region of p73. Six isoforms of p73 with differing C-terminal structures, alpha, beta, gamma, delta, epsilon and xi, have been reported. These variants differ in transcriptional activity on p53-responsive promoters. Here we report a possible mechanism of transcriptional activation by p73 splicing variants. C-terminal deletion mutants of p73 alpha showed a significantly higher level of transcriptional activity than wild-type p73 alpha, suggesting that the C-terminal structure of p73 alpha functions to repress the transcriptional activity of p73 alpha. The results of immunoprecipitation assays and two-hybrid assays in mammalian cells showed that the p73 variants interacted with each other, but not with p53. The transcriptional activity of p73 beta was reduced by co-expression with either p73 alpha or p73 epsilon, which bears an identical C-terminal structure to p73 alpha. Co-expression of the C-terminal portion of p73 alpha or p73 epsilon with p73 beta also resulted in reduced transcriptional activity. Moreover, we observed that the level of endogenous p21 protein induced by p73 beta was decreased by co-expression of full-length p73 epsilon or the C-terminal region of p73 alpha or p73 epsilon. These observations suggest that p73-mediated gene expression is regulated by the interactions of p73 splicing variants in the cell.
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PMID:Transcriptional activities of p73 splicing variants are regulated by inter-variant association. 1138 95

Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4^Cdt2 and SCF^Skp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4^Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability.
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PMID:DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. 2831 45