Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously described the development of radiation transformed human fetal prostate epithelial cells, 267B1. Using this in vitro model system, we investigated the molecular mechanisms of prostate carcinogenic progression by comparing nontumorigenic (267B1/B) and tumorigenic (267B1/D) cells. We examined the G1- to S-phase transition in synchronized cells to determine if the progression of 267B1 cells from nontumorigenic to tumorigenic was the consequence of a perturbation in the G1- to S-phase transition involving p53, pRb, p21, or p16. Nontumorigenic 267B1/B cells showed a time-dependent increase in the expression of p53 and a corresponding increase in p21 following exposure to ionizing radiation (6 Gy). The levels of pRb and p16 protein were virtually unchanged. In contrast, tumorigenic 267B1/D cells exhibited a p53-independent induction of p21 protein with a parallel increase in p16 protein in response to ionizing radiation, but no change in pRb was observed. These results suggest that the progression of 267B1 cells from nontumorigenic to tumorigenic involves p53-independent processes.
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PMID:p53-Independent tumorigenic progression of human prostate cells. 943 43

Characteristics of human hepatoma cell lines with the wild-type p53 were compared with those of human hepatoma cell lines with the mutant-type p53. The p21 protein located downstream of p53 was expressed in cell lines with the wild-type p53 but was not expressed in cell lines with the mutant-type p53. As to other tumor suppressor genes such as p16 and p27, there was no difference in their expression between both types of cell lines. In addition, no marked difference was observed in the activities of CDK2 and CDK4 between cell lines with the wild-type and the mutant-type p53. Phosphorylated Rb protein was detected in all cell lines except the HLE line, indicating that this cell line may have a deletion of and/or a mutation of the Rb gene. These results indicate that abnormalities of tumor suppressor genes other than p53, p16, p27, and Rb may be involved in hepatocarcinogenesis. The population doubling time of the wild-type p53 cells was significantly longer than that of the mutant p53 cells. Neither type of cell line showed a specific chromosome distribution which would indicate karyotype instability. The cell lines expressing the wild-type p53 produced tumors at lower frequency than those with the mutant p53 gene. Although there was no significant difference in effects of TGF-beta 1, EGF, cholera toxin, and db-cAMP on cell growth between the two types of cells, all three cell lines with the wild-type p53 were resistant to cytotoxicity of TNF-alpha, while two of the three with the mutant p53 were very sensitive to its cytotoxic effects.
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PMID:Comparison of cellular characteristics between human hepatoma cell lines with wild-type p53 and those with mutant-type p53 gene. 943 73

The senescent cell-derived inhibitor (sdi)-1 protein (p21 product) has been identified as a downstream mediator of the tumor suppressor p53 in the regulation of cell cycle progression through a G1 phase checkpoint. Given the importance of cell cycle inhibition for the treatment of restenosis, in this study we focused on the function of p21 gene in inhibiting proliferation of vascular smooth muscle cells (VSMC). To test the hypothesis, we transfected human p21 gene into human aortic VSMC using hemagglutinating virus of Japan-liposome-mediated transfer. Initially, we examined the successful transfection of human p21 gene into VSMC. p21 protein was increased in VSMC transfected with p21 vector as compared with control vector. Accompanied by increased p21 protein, transfection of p21 vector resulted in a significant decrease in number of VSMC induced by 2% serum (P<.01). Although p21 has been reported to play an important role in the regulation of apoptosis in some cells, apoptosis mediated by p21 is still controversial. Therefore, we hypothesized that overexpression of p21 mediates apoptosis in human VSMC, in addition to the blockade of cell cycle progression. First, we assessed the concordance between morphologic analysis and apoptosis as determined by nuclear staining with Hoechst 33342. Cells transfected with p21 gene exhibited the characteristic features of cell shrinkage, membrane blebbing, and rounding that are typical of apoptotic death. Of greater interest, a significant increase in apoptotic cells was observed in VSMC transfected with p21 vector as compared with control vector (P<.01). These results were confirmed by the measurement of DNA fragmentation. Consistent with nuclear staining, DNA fragmentation in VSMC transfected with human p21 gene was significantly increased as compared with that in VSMC transfected with control vector (P<.05). To study the molecular mechanisms of apoptosis mediated by overexpression of p21 gene, the protein levels of bax, a promoter of apoptosis, and bcl-2, an inhibitor of apoptosis, were also measured by Western blotting. Overexpression of p21 gene significantly increased protein of bax (P<.05), whereas transfection of p21 gene did not alter bcl-2 protein. Importantly, the ratio of bax to bcl-2 was significantly increased in VSMC transfected with human p21 vector as compared with control vector (P<.05). Overall, these results demonstrated that inhibition of VSMC growth by overexpression of human p21 gene was accompanied by induction of apoptosis through an inappropriate increase in bax protein. These results suggest that regulation of cell cycle by p21 may be closely linked to programmed cell death/apoptosis in human VSMC.
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PMID:Inhibition of growth of human vascular smooth muscle cells by overexpression of p21 gene through induction of apoptosis. 945 51

The WAF1/p21 gene product is an inhibitor of cyclin-dependent kinases which can be induced by the tumor suppressor p53 and mediate some of its effects, or function in p53-independent pathways of cell cycle regulation. Although a potential tumor suppressor gene, WAF1/p21 is expressed in bladder cancer. To elucidate the function of p21 in tumor cells we have investigated in urothelial carcinoma cell lines: i) WAF1/p21 mRNA and protein expression, ii) the biological effects of p21 overexpression or down-regulation and (iii) whether p21 can be induced by p53. WAF1/p21 mRNA levels examined in four cell lines were comparable to bladder mucosa. One cell line, HT1376, failed to express p21 protein due to a frame shift mutation. Overexpression of WAF1/p21 cDNA inhibited clone formation in three cell lines, whereas transfection with antisense WAF1 increased clone sizes and numbers. WAF1 sense clones showed diminished cell proliferation compared to the parental cell line. Apoptosis- induced wild-type p53 was not inhibited by overexpression of antisense WAF1/p21. In a cell clone derived from line VMCub1 by stable transfection with wild-type p53 under the control of a metallothionein promotor, p21 was induced along with p53 upon activation of the promoter with zinc chloride. This induction was accompanied by a decrease in cell proliferation but by little apoptosis. These data suggest that p21 inhibits proliferation in a p53-dependent or independent manner but does not mediate p53-induced apoptosis in urothelial carcinoma cells.
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PMID:WAF1/p21 regulates proliferation, but does not mediate p53-dependent apoptosis in urothelial carcinoma cell lines. 947 2

In order to clarify critical events during bronchial carcinogenesis, and to evaluate a possible prognostic role for p21 immunohistochemical detection, we assessed the immunohistochemical expression of p21 protein in 60 surgically resected non-small-cell lung cancers (NSCLCs) that had been investigated previously for their p53 protein status. We found that p21 protein was expressed in both normal and neoplastic tissue. In normal tissue, p21 immunoreactivity was detectable in a low percentage of well-differentiated cells. We found immunostaining for p21 in 80% of the investigated neoplasms. In 73.3% of the neoplasms, p21 was considered to be overexpressed. No relationship was found between p21 overexpression and tumor stage or tumor-nodal-metastatic (TNM) status. The histologic grading was slightly correlated with the p21 status (P = -0.51), with no significant differences noted between squamous carcinomas and adenocarcinomas. Survival percentage curves for our lung-cancer patients, based on a comparison of different p21 expression levels and constructed through a Kaplan-Meier analysis, showed significant differences in mean (P < 0.001) and overall (P < 0.001) survival time between patients of different p21 status, suggesting a favorable prognostic value of p21 immunostaining for NSCLC patients.
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PMID:p21waf1/cip1mda-6 expression in non-small-cell lung cancer: relationship to survival. 947 8

The inhibitor of cyclin-dependent kinases WAF1/p21 has been shown to mediate cell cycle arrest by p53 and other factors. We have studied its expression in urothelial carcinoma. Immunohistochemistry of paraffin-embedded tissues revealed no detectable p21 protein in normal mucosa, whereas 8 of 17 (47%) carcinomata in situ, 41 of 62 (66%) pTa, 14 of 30 (47%) pT1 and 5 of 15 (33%) muscle-invasive tumours stained positive, usually with a heterogeneous pattern. Expression of p21 was associated with low grade tumours. In contrast, the frequency of p53 accumulation increased with grade and stage as did the frequency of staining for the proliferation marker Ki67. The level of WAF1 mRNA was determined relative to beta-actin mRNA by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in 15 freshly frozen invasive tumours. In eight samples obtained from normal bladder mucosa, the values ranged from 0.93 to 2.19 arbitrary units (AU) (mean 1.54+/-0.37 AU), but varied widely from non-detectable to 16.21 AU (mean 3.02+/-4.44 AU) in the tumour specimens. In accord with the immunohistochemical findings, WAF1 mRNA expression was elevated over the range found in normal mucosa in 5 of 15 advanced tumours. In addition, RNA analysis revealed a decrease in expression in six tumours. No mutations were observed in the WAF1/p21 gene in these tumours, but two were heterozygous for the codon 31 polymorphism. These data indicate that p21 is frequently expressed in superficial, well differentiated urothelial carcinomas, but less often in muscle-invasive urothelial carcinomas, irrespective of their p53 status. The expression of p21 and its prevalence in low-stage tumours may reflect residual growth-regulatory influences potentially impeding but not necessarily inhibiting tumour development.
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PMID:Frequent and heterogeneous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma. 948 5

Several novel differentiated cell lines have been derived from a human hepatocarcinoma named HBG. Analysis of their functional properties evidenced a gradual differentiation process as they became confluent and a remarkable stability of the whole quiescent population for at least 6 weeks. However, when replated at low density after several weeks of quiescence, the differentiated cells were able to rapidly reverse to active proliferation, accompanied by transient dedifferentiation. Demonstration that the differentiated hepatic cells were growth-arrested in G1 phase was provided by the increased number of cells with 2C DNA content and decreased expression of S-phase markers. Characteristic features of oncogenes and cell cycle genes were defined during the differentiation process: (a) a biphasic expression of c-myc, with the latter wave covering the quiescence period; (b) opposite kinetics of c-Ki-ras and of N-ras expression with a pattern of changes paralleling that of c-myc; and (c) a decrease of cyclin D1 protein expression and of the cyclin D1-associated kinase activity. The mechanisms by which quiescent differentiated cells might reinitiate active proliferation were analyzed by studying several genes involved in cell growth and death regulation. We found: (a) a point mutation and loss of the specific activity of the tumor suppressor gene p53 without alteration of the apoptotic response to transforming growth factor beta1; (b) a gradual decrease of retinoblastoma protein, which was constantly present, mainly in a hyperphosphorylated form; and (c) an increase of cyclin-dependent kinase inhibitor p27 expression in confluent differentiating cells, as expected, whereas, surprisingly, a disappearance of the p21 protein was observed in parallel. These data may reflect specific mechanisms of cell cycle regulation in liver parenchymal cells through which these cells can proceed to control their reversible differentiation program.
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PMID:Cell cycle gene regulation in reversibly differentiated new human hepatoma cell lines. 948 53

New innovations are needed for the treatment of pancreatic cancer, as current treatments do not offer significant improvements in overall survival. p21WAF1--a tumor suppressor gene--acts as a downstream effector of p53 function and mediates G1 cell cycle arrest by inhibiting cyclin-dependent kinases, which promote cell growth. p21 expression has also been shown to increase more than 20-fold in senescent cells in culture. The replication-defective recombinant adenoviral system (rAd), a major innovation in gene transfer technology, has recently been used in gene therapy applications for various malignancies but not for pancreas cancer. In this study we used rAd-p21 in cell growth inhibition studies of pancreatic tumor cell lines in vitro to explore its potential as a prospective gene therapy for pancreatic adenocarcinoma. We studied two pancreatic cell lines in culture, HPAC and Hs766T. HPAC revealed higher endogenous levels of p21 gene expression at the protein and RNA levels compared to Hs766T. p21 induction was tested using different doses of rAd-p21 to establish an optimum dose for significant induction of p21 gene expression. Tumor cell growth in culture following rAd-p21 infection was also analyzed in both cell lines. HPAC and Hs766T cell lines showed a significant dose-dependent increase in p21 protein expression when infected with rAd-p21. Both cell lines showed significant growth arrest, but Hs766T showed less cell growth inhibition than HPAC cells. Flow cytometric cell cycle analysis of rAd-p21-infected cells showed a statistically significant increase in the number of cells in G0/G1 in HPAC cells. Similar results were also obtained in Hs766T cells, however, the data were not statistically significant. In conclusion, pancreatic tumor cell growth can be inhibited by rAd-p21 in vitro, with significant numbers of tumor cells reverting from S to G0/G1. Thus rAd-p21 may be effective as a candidate gene therapy for pancreatic cancer and should be further evaluated with in vivo studies.
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PMID:Inhibition of pancreatic tumor cell growth in culture by p21WAF1 recombinant adenovirus. 951 Jan 31

The occurrence of DNA double strand breaks induces cell cycle arrest in mortal and immortal human cells. In normal, mortal fibroblasts this block to proliferation is permanent. It depends on the growth regulator p53 and a protein p53 induces, the cyclin dependent kinase inhibitor, p21. We show here that following DNA damage in mortal fibroblasts, the induction of p21 and p53 is to a large degree shortlived. By 8 days after a brief exposure to DNA strand breaking agents, bleomycin or actinomycin D, p53 protein is at baseline levels, while the p53 transactivation level is only slightly above its baseline. By this time the concentration of p21 protein, which goes up as high as 100-fold shortly after treatment, is down to just 2-4-fold over baseline levels. Following the drop in p21 concentration a large increase in the expression level of the tumor suppressor gene p16INK4a is observed. This scenario, where a transient increase in p21 is followed by a delayed induction of p16INK4a, also happens with the permanent arrest that occurs with cellular senescence. In fact, these cells treated with agents that cause DNA double strand breaks share a number of additional markers with senescent cells. Our findings indicate that these cells are very similar to senescent cells and that they have additional factor(s) beside p21 and p53 that maintain cell cycle arrest.
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PMID:Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. 952 53

Many genes participate in the regulation of cell cycle progression from G1 to S phase. Functional loss of one or more of these genes has been reported to be associated with carcinogenesis and/or tumor progression and poor prognosis in many cancers. In a series of 126 patients with hepatocellular carcinoma (HCC), we immunohistochemically evaluated tumor expression of the cell cycle-related gene protein products of Rb, p21 (WAF1), and p53. Positive immunostaining for Rb, p21, and mutant p53 protein was detected in 58%, 33%, and 37% of the tumors, respectively. The proportion of HCCs exhibiting aberrant p53 protein expression increased significantly with advancing stage of disease (p < 0.001), poorer histological classification of differentiation (p < 0.01), and increasing tumor size (p < 0.01). A decrease in the proportion of HCCs expressing p21 protein was also associated with advancing clinical stage of disease (p < 0.01), and larger tumor size (p < 0.05). The only clinicopathological feature found to be associated with Rb status, was intrahepatic metastasis, which occurred with a higher frequency in HCCs exhibiting positive immunoreactivity for Rb protein expression (p < 0.05). Multivariate survival analysis revealed that, amongst the protein products of the different genes evaluated, only positive immunostaining for aberrant p53 protein expression served as an independent prognostic indicator, being significantly associated with worse survival in patients with HCC (p = 0.023). Analysis for relationships between gene products showed an inverse correlation between expression of aberrant p53 protein and p21 protein (p < 0.01), and also an inverse correlation between p21 protein and Rb protein expression (p < 0.05) in these cases of HCC. These findings demonstrate that positive immunostaining for mutant p53 protein expression is a significant indicator of tumor progression and poor prognosis, confirm that p21 protein expression is induced in a p53-dependent manner, and suggest that Rb protein expression may be regulated to some extent by p21 in HCC.
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PMID:Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma. 956 77


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