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)

Tumor suppressor p53 is a nuclear protein that is induced by DNA damage and is involved in G1 and G2 phase control of the cell cycle. p21WAF1/CIP1/SDI1 (p21), a cyclin-dependent kinase inhibitor, is a downstream target and effector of p53 to induce G1 arrest. Mimosine is a potent reversible late G1 phase blocker of the cell cycle. In this study, we showed that mimosine can increase both p21 mRNA and protein levels, indirectly inhibit cyclin E-associated kinase activity without affecting the cyclin E protein level, block human breast cancer cells (21PT) in the late G1 phase of the cell cycle, and induce a p53-independent p21 pathway in these cells. These results support the possibility of restoring a G1 checkpoint by use of mimosine. They also suggest that the mechanism of the effect of mimosine is complex and may have more than one target in the cell.
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PMID:p21WAF1/CIP1/SDI1 is elevated through a p53-independent pathway by mimosine. 880 7

To investigate the effect of p53 tumor suppressor gene loss in the mouse skin model of multistage carcinogenesis, p53 knockout mice, generated by gene targeting (p53 -/-), were mated to transgenic mice expressing v-rasHa (HK1.ras), v-fos (HK1.fos), or human transforming growth factor alpha+HK1.TGFalpha) exclusively in the epidermis, by means of a keratin K1-based targeting vector (HK1). HK1-p53 transgenic progeny expressing wild-type p53 alleles (p53 +/+) or hemizygous for the p53 knockout allele (p53+/-) were identical to parental HK1 lines and exhibited neonatal epidermal hyperplasia or wound-associated hyperplasia in adults, together with spontaneous or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced benign papillomas. Mating to p53-/- did not lead to the expected tumorigenesis in adults. Instead, whereas HK1.ras or HK1.TGFalpha transgenic mice null for p53 (HK1.ras-p53-/- and HK1.TGFalpha-p53-/-, respectively) retained the neonatal epidermal hyperplasia phenotype, in adults, spontaneous and TPA-promoted papilloma formation was blocked. Similarly, wound-associated epidermal hyperplasia/hyperkeratosis, a hallmark of adult HK1.fos phenotypes, was completely absent in HK1.fos-p53 -/- mice. Histological, immunofluorescence, and bromodeoxyuridine labeling analysis of neonatal or adult epidermis in HK1-p53 transgenic genotypes +/+, +/-, and -/- for p53 revealed no obvious differences in morphology, expression of keratinocyte differentiation markers, or mitotic index attributed to p53 loss. To determine whether the paradoxical absence of papillomas centered on up-regulation of p53 target genes, WAF1/CIP1/p21 RNA expression levels were examined in TPA promotion experiments. WAF1/CIP1/p21 expression increased in response to TPA promotion in all HK1-p53 transgenic genotypes regardless of p53 status. However, in HK1-p53 null genotypes, although TPA-induced, p53-independent WAF1/CIP1/p21 expression was observed, no large increase in expression was associated with the observed paradoxical tumorigenesis block. These data suggest that epidermis is somewhat resistant to the neoplastic effects of p53 loss, possibly possessing several compensatory systems. Alternatively, there may be a requirement forp53 expression in response to TPA or a wound-promotion stimulus in mouse epidermis.
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PMID:Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha. 881 35

We examined the relationship between expression of the p21 (WAF1/CIP1) inhibitor of cyclin-dependent kinases, cessation of proliferation, and terminal differentiation in the epithelia of the gastrointestinal tract. Using in situ hybridization, we performed a detailed study of patterns of p21 mRNA expression in different regions of the stomach, along the length of the intestine, and in tongue, cervix, and hair follicle. We detected strong hybridization only in cells that had ceased proliferation and begun the process of terminal differentiation. Induction of p21 transcription may serve as a useful marker for dissection of differentiation programs in these diverse epithelia. To determine the relative levels of p21 expressed in various regions of the gastrointestinal tract from the esophagus to the colon, we used quantitative RT-PCR with endogenous and exogenous sequences as internal standards. The highest levels of p21 expression were detected in the distal small intestine. To further investigate the role that cell cycle regulation may play during differentiation of intestinal epithelial cells, we examined the expression of p53, p21, cyclin D1, cyclin E, and E2F1 in the Caco-2 colon carcinoma cell line, which differentiates spontaneously after reaching confluence. p21 and p53 mRNA and protein levels increase as Caco-2 cells differentiate. In both undifferentiated and differentiated Caco-2 cells, p53 protein was not inducible by DNA damaging agents, suggesting the absence of functionally wildtype protein. Caco-2 cells should provide a useful model system for studying regulation of p21 and determining if it plays a role during intestinal epithelial cell differentiation.
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PMID:p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line. 883 53

The p53 gene product is part of a pathway regulating growth arrest at the G1 checkpoint of the cell cycle. Mutation of other components of this pathway, including the products of the ataxia telangiectasia (AT), GADD45, mdm2, and p21WAF1/CIP1 genes may have effects comparable to mutations in the p53 gene. The GADD45 gene is induced by ionizing radiation and several DNA-damaging xenobiotics. Induction requires the binding of wild-type p53 to an evoulutionarily highly conserved putative intronic p53 binding site in intron 3 of GADD45. We recently analyzed the entire coding region of the p53 gene in primary breast cancers of Midwestern white women and found 21 mutations among 53 tumors (39.6%). We now have shown by direct sequencing that there are no mutations in the intronic p53 binding site of the GADD45 gene in any of the 53 primary breast cancers and no mutations in the entire coding region of the GADD45 gene in a subset of 26 consecutive tumors (12 with p53 mutation and 14 without p53 mutation). The only sequence variation detected was a common polymorphism in intron 3. The absence of mutations in the GADD45 gene, including the putative p53-binding intronic site, suggests that this gene is not a frequent target of mutations in breast cancer. Although mutations of the p53 gene have been studied in a wide spectrum of human cancers, GADD45 has not been examined in any tumor or cell line to the best of our knowledge. Our results raise the possibility that mutation of the GADD45 gene alone is not functionally equivalent to loss of wild-type p53 activity.
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PMID:A polymorphism but no mutations in the GADD45 gene in breast cancers. 883 60

The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.
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PMID:Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2 kinase. 883 15

The treatment of chronic lymphocytic leukemia includes the use of alkylating agents, steroids, and more recently nucleoside analogues. While prior studies have described potential mechanisms of 2-chlorodeoxyadenosine cytotoxicity including the accumulation of DNA strand breaks and induction of apoptosis or programmed cell death, the expression of p53 and its downstream target WAF1/CIP1 have not been examined. In this report we describe the induction of p53 and WAF1/CIP1 in the apoptotic chronic lymphocytic leukemia cells after exposure to 2-chlorodeoxyadenosine.
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PMID:The induction of p53 and WAF1/CIP1 in chronic lymphocytic leukemia cells treated with 2-chlorodeoxyadenosine. 884 64

p21WAF1/CIP1 is a downstream effector of the p53 tumor suppressor gene and a universal cyclin-dependent kinase (CDK) inhibitor. To determine the ability of p21WAF1/CIP1 to function as a tumor suppressor, we constructed a replication-defective adenovirus vector containing p21WAF1/CIP1 (Adp21WAF1/CIP1) to effect ectopic overexpression in a p53-defective human astrocytoma cell line, U-373MG. We observed a marked decrease in CDC2 and CDK2 kinase activity associated with a corresponding decrease in the amount of CDC2 but not CDK2 protein; a decreased growth potential of Adp21WAF1/CIP1-infected cells demonstrated by diminished [3H]thymidine incorporation, increased cell doubling time and G1-arrested cell cycle; an association between Adp21WAF1/CIP1-infected cells and inhibition of aneuploid cell accumulation; and an alteration of the malignant phenotype of cells was evidenced by the loss of anchorage-independent growth in soft agar and the failure to induce tumorigenesis in both peripheral and intracerebral xenograft models, including the prevention of tumor formation Adp21WAF1/CIP1 infection 2 days post tumor cell implantation. Adp21WAF1/CIP1. Adp21WAF1/CIP1 appears to be a strong candidate for gene therapy studies based on these studies indicating that Adp21WAF1/CIP1 inhibits proliferation, tumorigenicity and aneuploidy in human brain tumor cells.
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PMID:Effects of ectopic overexpression of p21(WAF1/CIP1) on aneuploidy and the malignant phenotype of human brain tumor cells. 887 77

Proteasome-dependent degradation of regulatory proteins is a known mechanism of cell cycle control. We found that the proteasome-specific inhibitor lactacystin (LC) induced expression of the cell cycle inhibitor p21WAF1/CIP1 in human cancer cells regardless of their p53 status. Both wild-type (wt) p53 and p21 protein levels increased by two hours in wt p53 containing cells, whereas mutant (mt) p53 levels decreased and the increase in p21 levels was delayed to 6 hr following inhibition of proteolysis by LC in mt p53 expressing cells. We found that wt but not mt p53 expressing cells increased p21 mRNA and p21-promoter reporter levels following LC exposure, suggesting transcriptional induction of p21. Inhibition of protein synthesis by cycloheximide demonstrated increased p21 protein half-life in the presence of LC in mutant p53 containing cells. p21 induction was correlated with the cytostatic effects of LC. The results suggest that p21 protein expression could be increased by transcriptional mechanisms as well as inhibition of proteolysis by LC.
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PMID:Proteasome-dependent regulation of p21WAF1/CIP1 expression. 887 53

The tumor suppressor gene p53, implicated in diverse types of human tumors, functions both as a gene-specific transcription factor as well as a specific inhibitor of the transcription of certain genes. The two physiological outcomes of re-expression of wild type p53 in tumor cells, not expressing wild type p53, are G1 arrest and apoptosis. The mechanism of G1 arrest by p53 is much better documented than its ability to trigger apoptosis. P53 as a transcription factor induces the expression of p21WAF1/CIP1/Sdi1, an inhibitor of the cyclin dependent kinases (CDKs)2, 3, 4 and 6. Thus, a G1 arrest can result simply by the p53 induced expression of p21WAF1/CIP1/Sdi1. Amongst the other genes presently characterized to be regulated by p53 are BAX, a homologue of the BCL-2 gene. Bax does not trigger apoptosis, but simply accelerates the rate at which apoptosis proceeds54. P53 also down regulates the expression of cyclin A, providing a secondary break on cell cycle progression into the through the S phase.
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PMID:The role of p53 in cell cycle regulation. 888 Aug 67

p21 (WAF1/CIP1) protein expression in various thyroid tissues, including thyroid carcinoma, was studied by means of immunohistochemistry using anti-p21 monoclonal antibody. Normal follicles and hyperplasias rarely expressed p21, whereas immunohistochemically positive cells were also too rarely found in follicular adenomas to justify these cases being classified as positive. Twenty eight of the 93 carcinomas examined (30.1%), however, were positive for p21. Of the p21-positive cases, 80% of the undifferentiated and 28.6% of the poorly differentiated carcinomas showed lesions co-expressing p21 and p53. If diffuse immunoreactivity of p53 reflects the p53 mutation, our results indicate that p21 in these carcinomas can be induced by p53-independent as well as by p53-dependent pathways. On the other hand, well-differentiated carcinomas did not co-express these two proteins and it therefore remains unclear whether p53-independent or p53-dependent pathways are predominant in this type of carcinoma. The incidence of expression of p21 was very similar in undifferentiated (26.3%), poorly (28.0%) and well-differentiated carcinomas (32.7%), even though they are characterised by different degree of malignancy. Furthermore, no correlation between p21 expression and either clinical parameters or patient's prognosis could be established. These results suggest that p21 is only marginally related to the characteristics of thyroid carcinoma and can play only an adjuvant role in regulating the progression of this carcinoma.
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PMID:Expression of p21 (WAF1/CIP1) protein in clinical thyroid tissues. 888 16


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