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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have analyzed the antiproliferative activity of the p53 tumor suppressor gene in human tumor cell lines harboring activated ras genes. The levels of p53 protein and incorporation of bromodeoxyuridine in transiently transfected cells were determined simultaneously by flow cytometry. The human HT1080 fibrosarcoma, EJ bladder carcinoma, and SW480 colon carcinoma cell lines were equally sensitive toward wild-type p53-mediated inhibition of DNA synthesis, independent of the state of the endogenous p53 protein. Overexpression of p53 genes mutated at amino acid codon 143 resulted in increased proliferation of SW480 cells, which have two mutated endogenous p53 alleles. To mimic the genetic constitution of an evolving tumor cell that has sustained a mutation in one p53 allele, we coexpressed both wild-type and mutant p53 genes controlled by strong viral promoters in HT1080 cells. Transiently transfected cells showed a reduced bromodeoxyuridine uptake similar to cells into which only wild-type p53 had been introduced. The wild-type p53 gene is a dominant growth suppressor over the mutant in all three different cell lines analyzed. By immunoprecipitation with antibodies PAb 122, PAb 420, and PAb 1620, we demonstrate the presence of both the mutant and wild-type conformations of the p53 protein in the transfected cells.
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PMID:Functional interaction of wild-type and mutant p53 transfected into human tumor cell lines carrying activated ras genes. 827 55

Genetic and molecular abnormalities, in association with malignant phenotypes, have been previously demonstrated in a variety of human tumors. Although the multistep theory fits well for some cancers such as retinoblastoma and colon carcinoma, for many others it still remains to be proven. Neuroblastoma, a tumor found in pediatric patients, seems to fall into the multistep model. Nonrandom chromosome abnormalities have been found with 1p deletion, loss of heterozygosity for short arm of chromosome 1 and for chromosome 11q and 14q. Amplification of N-myc oncogene and an increased level of Ras protein have also been demonstrated. Therefore, even if it is not possible to show that these mutations happen as discrete events in their order of appearance, the multistep model seems involved in neuroblastoma development. Neuroblastoma has a peculiar aspect, however, that makes this tumor a natural model of defect of cell differentiation. In fact, there is a particular subset of metastatic tumors that show spontaneous regression. In vitro, neuroblastoma cell lines can be induced to differentiate along the neural pathway using retinoic acid. Other natural and chemical substances are also able to induce cell differentiation. During retinoic acid treatment, N-myc oncogene expression decreases and other genes are deregulated. p53 and MDR1 gene expression increases. These two different aspects, failure of cell differentiation pathway and genetic mutations, make the neuroblastoma one of the most difficult problems of modern molecular biology.
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PMID:Neuroblastoma: the result of multistep transformation? 840 Dec 51

Loss of heterozygosity (LOH) on chromosomes 1p, 4q, 5q, 8p, 13q, 16q, 17p, and 22q, and mutation of the p53 gene were simultaneously analyzed in 63 hepatocellular carcinomas (HCCs) with distinct histopathological grades, 80% of the tumors being from patients who had been exposed to hepatitis B virus (HBV) or hepatitis C virus (HCV). The frequencies of LOH on 8 chromosomes were 0-25% in 10 well differentiated HCCs, LOH being observed on 4q, 5q and 17p, 21-53% in 26 moderately differentiated HCCs, LOH on 8p and 17p being high, and 29-75% in 27 poorly differentiated HCCs, LOH on 17p, 4q and 8p being the most frequent. p53 gene mutation was detected in moderately and poorly differentiated HCCs at 15% and 52%, respectively, but not at all in well differentiated HCCs. Of the mutations detected, 42% were transition mutation and only 5% were CpG transition, in contrast to the high frequencies of these types of mutations in colon tumors (78% and 54%, respectively). LOH on every chromosome and p53 mutation were more frequent in more advanced tumors, and accumulation of genetic changes increased with increase of the histopathological grade. Frequency of genetic changes in HCCs from HBV-positive patients was comparable to that from HCV-positive patients. The present results suggest that accumulation of genetic changes in multiple tumor suppressor genes, especially LOH on 17p, 4q and 8p, and mutation in p53 gene, are involved in the progression of liver cancer, and LOH on 17p and 4q precedes other genetic changes. Differences in the direction of p53 mutation between HCC and colon carcinoma suggest that liver carcinogens are distinct from colon carcinogens. Furthermore, mechanisms affecting the frequency of LOH in HCCs in HBV-infected patients may be similar to those in HCV-infected patients.
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PMID:Genetic changes and histopathological grades in human hepatocellular carcinomas. 840 53

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.
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PMID:Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene. 843 70

The ability of exogenous p53 tumor-suppressor and activated N-PAS oncogene to influence differentiation state of human colon carcinoma LIM 1215 cells and their derivatives with acquired resistance to actinomycin D or methotrexate was analysed Introduction of retroviral construct expressing human wild-type (wt) p53 into LIM 1215 cells induced electron microscopic manifestations of enterocytic differentiation, i.e. caused an increase in the numbers of cells with microvilli, desmosomes and glandular-like lumens. Mutations at codons 248 or 273, the most frequent p53 changes in primary colorectal cancer, partially abrogated the ability of p53 to stimulate differentiation of LIM 1215 cells. Human M-PASasp12 showed stronger stimulation of cell differentiation as compared to p53wt. Especially high proportion (> 80%) of cells possessing pronounced manifestations of columnar enterocytic differentiation was observed after introduction of PAS-expressing construct into methotrexate-resistant LIM 1215 cell subline that originally demonstrated higher maturation than parental cell line. In cell subline with two introduced genes, activated PAS and mutant p53His273, the number of differentiated cells was similar to that observed in cell culture containing only PAS-construct. However, these two sublines differed in the quantity of desmosomes as well as in carcino-embryonic antigen (CEA) expression. Comparison of expression of different electron microscopic features of cell differentiation and CEA expression in cell sublines selected for methotrexate-resistance and/or expressing exogenous constructs allows to suppose that p53 tumor-suppressor, PAS oncogene and dhfr gene amplification may lead to somewhat distinct differentiation states.
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PMID:[Stimulation of differentiation of LIM 1215 large intestinal tumor cells during expression of the p53 exogenous antioncogene or the activated ras oncogene]. 857 93

The tumor growth suppressor p21 has been shown to be induced by wild-type p53 (wt-p53) and to be a potent inhibitor of cyclin-dependent kinases and PCNA/DNA polymerase delta. Although wt-p53 is reported to be phosphorylated by several protein kinases, the function and significance of the phosphorylation of wt-p53 are not yet fully understood. Using OK-1035, a selective inhibitor of DNA-dependent protein kinase (DNA-PK), we demonstrated the importance of the phosphorylation of wt-p53 by DNA-PK in the DNA damage-mediated expression of the p21 gene. Treatment of HCT116, a human colon carcinoma cell line, with adriamycin induced the expression of wt-p53 and p21. By addition of OK-1035 to this culture, the induction of p21 protein was significantly decreased in a dose-dependent manner, whereas wt-p53 induction was not affected. Northern blot analysis revealed that suppression of p21 protein expression by OK-1035 resulted from reduction in the level of p21 mRNA. OK-1035 did not directly affect the binding ability of wt-p53 to its consensus DNA sequence. Our observations support the idea that wt-p53 induces the transcriptional activation of the p21 gene only after it is phosphorylated by DNA-PK.
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PMID:DNA-dependent protein kinase inhibitor (OK-1035) suppresses p21 expression in HCT116 cells containing wild-type p53 induced by adriamycin. 861 35

DNA-damaging agents such as ionizing radiation (IR) activate the tumor suppressor p53, and, in turn, p53 transactivates a number of downstream effector genes such as GADD45, CIP1/WAF1, and MDM2. The induction of these downstream genes following IR appears to be strictly dependent upon the presence of wild-type functional p53 known to evoke G1 arrest. In this study, we characterized 56 cell lines from 9 different tumor types with predetermined p53 genotype by measuring the induction of GADD45, CIP1/WAF1, and MDM2 relative mRNA levels after IR. A higher fraction of melanoma lines had wild-type (wt) p53 (5/8, or 63%) compared to the nonmelanoma lines (11/48, or 23%). Most wt p53 (nonmelanoma) cell lines (11/12, or 92%) showed clear induction of both GADD45 and CIP1/WAF1. On the other hand, many wt p53 melanoma lines (4/5, or 80%) showed normal induction of CIP1/WAF1, but little or no induction of GADD45. Despite this defect in GADD45 induction, we found that all wt p53 melanoma lines exhibited strong G1 arrest and increased levels of p53 protein after IR. The results demonstrated that radiation-induced G1 arrest could occur by the p53-CIP1/WAF1 pathway without appreciable induction of GADD45 in melanoma lines. Time course experiments demonstrated prolonged induced expression of CIP1/WAF1 mRNA transcripts in melanoma lines in which GADD45 induction was lacking, suggesting some sort of compensatory mechanism involving CIP1/WAF1, in cell lines with defective GADD45 induction. We could reproduce this compensatory effect in RKO colon carcinoma cells in which GADD45 expression was blocked by constitutive antisense vectors. These findings reveal that defective induction of GADD45 following IR is common in human melanoma cell lines.
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PMID:An abnormality in the p53 pathway following gamma-irradiation in many wild-type p53 human melanoma lines. 863 Oct 22

The LoVo colon carcinoma cell line that presents two wild type p53 alleles was used as the recipient for a series of transfections with p53 expression vectors coding for wild-type or three different mutants (143ala, 175his or 273his). The parental cell line as well as all clones that had rearranged the plasmid with consequent loss of p53 c-DNA were readily blocked at the G1/S boundary following 10 Gy of irradiation. For each mutation two clones with different levels of mutant protein expression were selected. Confirmation of the integration of the exogenous sequence was obtained by the expression of the mutant m-RNA, established by reverse transcription and DGGE or Southern blot. Flow cytometric measurements of 5-bromodeoxyuridine incorporation revealed a total G1/S block of the 143ala transfectants, similarly to the parental and control transfectant cells, but little or no cell cycle block for the 175his and 273his clones. Although it has been shown in vitro that all three mutations interfere with transcriptional activation by the wild-type protein, not only did we observe p53 protein induction and nuclear accumulation following irradiation, but WAF-1/CIP-1 m-RNA was increased in some of the clones for which the G1/S block was abolished. Our results show that mutant p53 proteins are to some extent submitted to the control of the cellular environment in cancer cells with wild type p53 alleles, but with an efficacy that depends on the mutation.
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PMID:Different p53 mutations produce distinct effects on the ability of colon carcinoma cells to become blocked at the G1/S boundary after irradiation. 863 10

The endogenous expression of p53 and p53-regulated genes has been examined in a thymidylate synthase-deficient colon carcinoma cell line (TS-) and a derived mutant clone (Thy4) that exhibit acute or delayed apoptotic responses, respectively, when released from G0 synchrony under conditions of dThd starvation. These cell clones demonstrate heterozygosity in p53, thereby expressing one wt allele and one with an A-->C point mutation at codon 240. Following release from G0, upregulated expression of both alleles occurred. During apoptosis in TS-, a wtp53 phenotype was expressed and in Thy4 during cytostasis, a mp53 phenotype was manifested, as determined from the ratios of wtp53/mp53 proteins, transactivation of p50-2 (a wtp53-responsive CAT reporter construct) and the endogenous expression of MDM2. Neither cytotoxicity nor cytostasis correlated with expression of p21Waf1/Cip1 Thy4 cells sustained accumulation of high levels of Bax in a wtp53-independent and dThd-independent manner and survival was associated with upregulated expression of Bcl-2. In contrast, Bax expression decreased in TS- during apoptosis, except in a highly resistant subpopulation that retained high levels of Bax. Data suggest that resistant cells (Thy4) can sustain high Bax expression and that Bcl-2 is upregulated in response to an apoptotic stimulus due to the absence of negative regulation by wtp53.
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PMID:Acute and delayed apoptosis induced by thymidine deprivation correlates with expression of p53 and p53-regulated genes in colon carcinoma cells. 866 31

In order to clarify the association between bcl-2 protein (Bcl-2) expression and genetic alteration, we investigated p53 and DCC (deleted in the colon carcinoma gene locus) gene abnormalities in Bcl-2-positive and -negative gastric carcinomas using a polymerase chain reaction/loss of heterozygosity (LOH) assay. Bcl-2 immunoreactivity was found in 25 of 178 (14%) gastric carcinoma cases. With these 25 positive cases, the proportion 18/87 (20.6%) of the total in early stages demonstrating invasion of the mucosa and/or submucosa was significantly greater (P = 0.013) than the 7/91 (7.7%) found for advanced tumors exhibiting invasion into or through the muscularis propria. However, there was no statistically significant variation between the proportions for differentiated (17/98 cases, 17.3%) and undifferentiated (8/80 cases, 10%) lesions. Sixteen Bcl-2-positive cases (9 cases were not studied because of insufficient specimen material to allow extraction of DNA) and 31 cases randomly selected from a Bcl-2-negative group were analyzed for the presence of p53-LOH or DCC-LOH and for p53 by immuno-histochemistry. The minority of the Bcl-2-positive group had p53-LOH and were immunopositive for p53 (P = 0.033, P = 0.028 respectively), while no association was found in the Bcl-2-negative category. In contrast, there was no correlation at all between Bcl-2 expression and DCC-LOH although the number of informative cases analyzed was too small to allow definite conclusions. These results indicate that Bcl-2 may be predominantly expressed at an early stage in gastric carcinomas, possibly in negative association with p53 gene abnormalities.
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PMID:Bcl-2 expression and allelic loss of the p53 gene in gastric carcinomas. 869 Jul 54


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