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)

p53 induction and cell cycle arrest occur following DNA damage, possibly to allow repair prior to replication. p21WAF1/CIP1, a cyclin-cyclin-dependent kinase inhibitor and proliferating cell nuclear antigen-interacting protein, is induced by p53 and mediates the cell cycle arrest. To investigate a role for p21 in DNA repair in vivo, we studied the expression of in vitro damaged reporter DNA transfected into p21 +/+ or -/- HCT116 human colon cancer cells. Introduction of UV-damaged or cisplatinum-damaged cytomegalovirus-driven beta-galactosidase reporter DNA into tumor cells revealed a significant decrease (2-5-fold) in reporter expression in p21 -/- versus +/+ cells. In the absence of DNA damage, there was a significant increase (2-3-fold) in the number of 6-TG-resistant colonies derived from p21 -/- versus +/+ cells. Reintroduction of wild-type p21, but not a p21 C-terminal truncation mutant which lacks the proliferating cell nuclear antigen interaction domain, stimulated (2-3-fold) the repair capacity of the p21-deficient cells. We conclude that p21 deficiency is associated with a defect in DNA repair, which could lead to an increased sensitivity of tumor cells to DNA damage.
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PMID:Repair Defect in p21 WAF1/CIP1 -/- human cancer cells. 862 93

In this study, human and rat cancer cells were used to investigate the expression of p53 and p21/WAF1/CIP1 and their association with apoptosis after exposure to nitric oxide (NO). It was found that NO induced nuclear accumulation of p53 protein in a dose- and time-dependent manner. The level of p53 protein was elevated by about fivefold compared with that of mock-treated cells 48 h after exposure to 300 ppm NO. The induction of p53 by NO was found by pulse-chase analysis to be mainly regulated by post-translational modification. The correlation between p53 status and apoptosis induced by NO in human cancer cells was also investigated in this study. We found that apoptosis was easily induced in cells containing wild-type p53 (COLO 205 and Hep G2) after exposure to NO. The p21/WAF1/CIP1 protein was induced by NO in cells containing wild-type p53 (Hep G2) but not in cells without p53 (Hep 3B) or with mutated p53 (HT-29). Our results indicate that wild-type p53 and p21/WAF1/CIP1 expression was elevated in human cancer cells by exposure to NO and suggest that this may eventually promote apoptosis.
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PMID:Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. 863 91

The expression of the WAF1/CIP1 gene product, p21, in enzyme-altered foci (EAF) induced by diethylnitrosamine (DEN) and phenobarbital (PB) was examined. p21 expression in the nucleus of hepatocytes in EAF was decreased compared to surrounding tissue. Fifty-eight percent of all GST-P-positive EAF induced by DEN and 79% of the EAF induced by PB were p21-negative. The proportion of p21-negative EAF increased with the size of the foci and more than 90% of the largest EAF were p21-negative. p21 is a mediator of p53 signals leading to block of the cell cycle. In conjunction with previous data indicating that p53 is not induced in GST-P-positive hepatocytes isolated from EAF-bearing rats, the results of this study suggest a role for altered signaling in the G1-S check point in rat hepatocarcinogenesis.
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PMID:Low expression of the WAF1/CIP1 gene product, p21, in enzyme-altered foci induced in rat liver by diethylnitrosamine or phenobarbital. 864 Jul 40

We have examined microsatellite instability and loss of p53 function in human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independent cisplatin-resistant sublines are RER(+), whereas the parental line shows no evidence of microsatellite instability. Microsatellite mutations in random, nonselected subclones of a cislatin-resistant line are observed in the absence of further drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather than being transiently induced by DNA damage. Furthermore, a cisplatin-resistant derivative shows reduction in a G:T mismatch recognition activity compared to the parental line. Independent lines selected by multiple exposure to cisplatin show resistance factors of up to a 5-fold by clonogenic assay and have reduced cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of loss of p53-dependent functions, as measured by a loss of radiation-induced G(1) arrest and reduced CIP1 mRNA. Induced loss of p53 function by transfection of mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that tolerance of DNA damage and expansion of cells with an RER(+) phenotype may select for reduced ability to engage apoptosis and loss of p53 function.
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PMID:Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells. 864 Aug 28

We previously reported that introduction of the wild-type p53 gene into human cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer for p53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, significantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.
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PMID:The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers. 864 47

Mutations in the WAF1/CIP1 gene were not found in 36 ovarian carcinomas, including tumours with loss of heterozygosity at the WAF1/CIP1 locus and/or lacking p53 mutations. In addition, no association was demonstrable between a polymorphism in a conserved region of the WAF1/CIP1 gene and ovarian carcinoma.
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PMID:WAF1/CIP1 structural abnormalities do not contribute to cell cycle deregulation in ovarian cancer. 864 86

HPV-immortalized human oral keratinocytes can convert to tumorigenic cells when exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but normal human oral keratinocytes cannot transform with a similar exposure. The different responses of these cells could be due to different genetic stability of cells. In as much as genetic stability is determined by cell cycle control and of repair of damaged DNA, we studied the effect of MNNG exposure upon cell cycle progression, expression of p53, WAF1/CIP1 and gadd45, and the mutation frequency of a shuttle vector pS189 in normal human oral keratinocytes, in HPV-immortalized oral keratinocytes, and in an oral cancer cell line expressing mutant p53. Normal cells demonstrated transient cell cycle arrest after exposure to MNNG, but the other tested cells did not. While MNNG exposure significantly increased the levels of intranuclear wt p53 protein and the expression of WAF1/CIP1 and gadd45 genes in normal cells, it did not alter them in the immortalized and cancer cells. The mutation frequency of pS189 plasmid was significantly lower in normal cells than in the other tested cells. These data indicate that malignant conversion of HPV-immortalized oral keratinocytes may, in part, be associated with the cells' genetic instability. The genetic instability may be due to cells' (1) inability to accumulate intranuclear wt p53 to a threshold level at which p53 upregulates the transcription of WAF1/CIP1 and gadd45, resulting in the loss of cell cycle control and (2) inefficient repair of DNA damage caused by genotoxic agents.
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PMID:Oncogenic transformation of HPV-immortalized human oral keratinocytes is associated with the genetic instability of cells. 864 1

p21, the product of the WAF1/CIP1/SDI1/mda-6 gene, is an inhibitor of cyclin-dependent kinases. In cell cultures p21 is induced by p53-dependent and p53-independent pathways by DNA damage and induction of differentiation. We investigated p21 RNA and immunohistochemical expression in 43 non-small cell lung carcinomas and corresponding normal lung samples previously investigated for p53 and WAF1 gene status and p53 protein expression. p21 RNA and protein expression in normal and neoplastic tissues were strictly associated (p-0.0001). In normal tissue p21 RNA was expressed at low levels and p21 immunoreactivity was seen in scattered differentiated bronchial, alveolar and stromal cells. In the majority of neoplasms p21 protein and RNA were expressed at higher levels than in the corresponding normal tissues: p21 overexpression was seen in 27 (63%) and 28 (65%) cases respectively. p21 was expressed independently from p53 gene/protein alterations. p21 overexpression was more frequent in well differentiated tumors (P=0.01 and P=0.022 for RNA and protein respectively), and p21 immunoreactivity was usually seen in foci of more pronounced differentiation. We conclude that p21 expression is related to tumor differentiation, and that p53-independent p21 expression is a common feature of in vivo neoplasms.
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PMID:p21 RNA and protein expression in non-small cell lung carcinomas: evidence of p53-independent expression and association with tumoral differentiation. 864 34

Human p21 (also known as WAF1, CIP1, or SDI1) is a dual inhibitor of cyclin dependent kinases (CDKs) and the replication factor PCNA, which plays a role as a downstream mediator of the cell-cycle arrest induced by the tumor suppressor p53. To determine whether inactivation of downstream targets of p53 might contribute to cellular transformation, we have examined the integrity of the p21 gene in 36 invasive ductal breast carcinomas. Direct sequence analysis of the polymerase chain reaction-amplified p21 gene revealed a C to T transition in codon 94 that caused the substitution of a tryptophan for an arginine in a tumor specimen. This mutation was not detected in normal DNA extracted from the same patient nor in a polymerase chain reaction-restriction fragment length polymorphism of 50 unrelated individuals, indicating that it corresponds to a tumor-specific alteration. Functional analysis of the p21(R94W) protein produced in different eukaryotic and prokaryotic expression systems revealed that this mutation impaired the ability of p21 to inhibit CDKs. By contrast, the R94W mutant was unaltered in its ability to promote cyclin-CDK association as well as in its ability to bind proliferating cell nuclear antigen, thus leaving its putative functions as kinase activator or as inhibitor of replicative DNA synthesis intact. On the basis of these functional analysis, we propose that the Arg residue at position 94 is important for the CDK inhibitory role of p21.
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PMID:Functional analysis of a p21WAF1,CIP1,SDI1 mutant (Arg94 --> Trp) identified in a human breast carcinoma. Evidence that the mutation impairs the ability of p21 to inhibit cyclin-dependent kinases. 866 32

The involvement of p53 protein in cell differentiation has been recently suggested by some observations made with tumor cells and the correlation found between differentiation and increased levels of p53. However, the effect of p53 on differentiation is in apparent contrast with the normal development of p53-null mice. To test directly whether p53 has a function in cell differentiation, we interfered with the endogenous wt-p53 protein of nontransformed cells of two different murine histotypes: 32D myeloid progenitors, and C2C12 myoblasts. A drastic inhibition of terminal differentiation into granulocytes or myotubes, respectively, was observed upon expression of dominant-negative p53 proteins. This inhibition did not alter the cell cycle withdrawal typical of terminal differentiation, nor p21(WAF1/CIP1) upregulation, indicating that interference with endogenous p53 directly affects cell differentiation, independently of the p53 activity on the cell cycle. We also found that the endogenous wt-p53 protein of C2C12 cells becomes transcriptionally active during myogenesis, and this activity is inhibited by p53 dominant-negative expression. Moreover, we found that p53 DNA-binding and transcriptional activities are both required to induce differentiation in p53-negative K562 cells. Taken together, these data strongly indicate that p53 is a regulator of cell differentiation and it exerts this role, at least in part, through its transcriptional activity.
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PMID:Interference with p53 protein inhibits hematopoietic and muscle differentiation. 869 14


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