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

The p53 tumor-suppressor gene is the most commonly altered gene in human cancers. Here we demonstrate that transcripts of the mdm2 gene, which encodes a cellular p53 binding protein, markedly increased in the rat liver within 1 to 3 h, reached a peak at 12 h and returned to the basal level 48 h after the administration of carbon tetrachloride. However, the level of hepatic mdm2 mRNA did not significantly change after partial hepatectomy. This is in contrast to p53 gene expression which increased after either procedure. C-myc transcripts also rapidly increased after the injection of carbon tetrachloride, reaching a maximal level at 3 h. The activity of serum alanine aminotransferase was low within the first 12 h and was maximal 24 h after carbon tetrachloride. These results suggest that the transient hepatic expression of the mdm2 gene prior to the onset of cell death is more likely to reflect events associated with necrosis rather than with cell proliferation.
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PMID:Expression of the protooncogene mdm2 markedly increases in response to carbon tetrachloride but not after partial hepatectomy in contrast to p53. 766 43

The p53 gene, located on chromosome 17p 13.1 and coding for a nuclear 393 amino-acids phosphoprotein acts to constrain or antagonize cell growth, and as such, is a tumor suppressor gene. In fact, inactivation of p53 tumor suppressor gene is a common event in the development of all or most types of human cancers. About half of cell cancer cases analysed thus far involve missense mutation of one p53 allele combined with the deletion of the second allele, and many of the remaining cases involve a functional inactivation of p53 protein through non mutational mechanisms. The importance of p53 as an inherited cancer susceptibility gene has been demonstrated in Li-Fraumeni syndrome. In some circumstances, it has been shown that in response to DNA damage, the p53 level in the cell increases considerably and induces a cell growth arrest late in G1 phase. This cycle arrest allows the altered DNA to be repaired before entry of the cell into S phase. This function of p53 helps to insure the genomic stability of the cell. Mutations in p53 eliminate this response and result in enhanced frequency of genomic rearrangements. In other circumstances wild type p53 may act by triggering cell death by apoptosis. The p53 protein exerts its physiological functions through various biochemical activities. These include its ability to be a site-specific transcriptional transactivator as well as a repressor of transcription. The oncoproteins derived from several oncogenic DNA viruses including SV40 large T antigen, the adenovirus E1B protein, and papillomavirus E6 protein, as well as specific cellular gene products e.g. mdm2 form complexes with the p53 protein, causing its inactivation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[P53 and cancers]. 767 43

The reversibility of a differentiation program termed dedifferentiation, redifferentiation, or retrodifferentiation opens a spectrum of new possibilities for cellular development. During differentiation and retrodifferentiation, the expression of gene products associated with a differentiated phenotype and cell cycle regulation demonstrate inverse patterns. This effect requires a coordinated network that simultaneously controls cell growth and differentiation. In particular, crosstalk between induction of differentiation and G0/G1 cell cycle exit can be initiated and sustained by activated serine/threonine kinases and tyrosine kinases. Phosphorylation signals are relayed to certain genes or transcription factors such as Fos/Jun, EGR-1, NF-kappa B, MyoD, or the Myc/Max gene family. However, the precise regulation of these transcription factors to confer signals to differentiation-associated and cell cycle-regulatory genes remains unclear. Cell cycle exit into a transient G0'-arrest cycle or a terminal G0 phase is determined by a network of phosphorylation signals involving the retinoblastoma protein and a variety of factors such as the E2F family, cyclins, and cyclin-dependent kinases. In this context, a variety of differentiation-induced cell lines, including monocytic, neuronal, or muscle cells, can progress through the G0'-arrest cycle, whereby a certain population retains the capacity to retrodifferentiate and reenter the cell cycle. In contrast, the rest of the differentiated population enters the irreversible G0 phase (terminal commitment) that finally results in programmed cell death. The expression of growth arrest-specific (gas and gadd) genes is associated with the G0'-arrest cycle, and other factors, including c-myc, p53, mdm2, and bcl2/bclx, contribute to the regulation of the cell death program. Although the precise signaling cascade determining retrodifferentiation or cell death remains unclear, a coordinated inter- and intracellular regulation could establish a certain biological balance between these exclusive pathways. Consequently, a retrodifferentiation process may provide a potential for cell type conversion or transdifferentiation, whereby retrodifferentiated cells can be induced to develop via a different pathway according to tissue-specific requirements.
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PMID:Retrodifferentiation and cell death. 771 Nov 13

Epstein-Barr virus (EBV) efficiently converts resting human B cells into actively cycling, immortal, lymphoblastoid cell lines (LCLs). Here we show that LCLs expressing the full complement of latent viral genes are very sensitive to DNA-damaging agents such as cisplatin. The response includes a rapid accumulation of the tumour suppressor protein p53 and induction of the cellular genes mdm2 and WAF1/p21. Although the levels of Bcl2 protein and Bax mRNA appear unaltered by the activation of p53, within 24 h the majority of cells undergo apoptosis. Over-expression of wild-type p53 in an LCL also resulted in apoptosis; this was preceded by the dephosphorylation of the retinoblastoma gene product, pRb. Primary resting B cells showed no response to cisplatin and even after drug treatment, p53 remained undetectable. However, after infection with EBV, p53 gene expression was induced to a similar level to that found in mitogen-activated B cells. When the physiologically activated primary B cells were exposed to cisplatin, although p53 accumulated as in LCLs, the outcome was growth-arrest rather than gross cell death. We conclude that, in contrast to the transformation of fibroblasts by adenovirus, SV40 or HPV, when B cells become activated and immortalized by EBV they are sensitized to the p53-mediated damage response. When the resulting LCLs are treated with genotoxic agents such as cisplatin, they are unable to arrest like normal cells because they are driven to proliferate by EBV and consequently undergo apoptosis.
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PMID:Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. 772 16

Employing the myeloblastic leukemia M1 cell line, which does not express endogenous p53, and genetically engineered variants, it was recently shown that activation of p53, using a p53 temperature-sensitive mutant transgene (p53ts), resulted in rapid apoptosis that was delayed by high level ectopic expression of bcl-2. In this report, advantage has been taken of these M1 variants to investigate the relationship between p53-mediated G1 arrest and apoptosis. Flow cytometric cell cycle analysis has provided evidence that activation of wild-type (wt) p53 function in M1 cells resulted in the induction of G1 growth arrest; this was clearly seen in the M1p53/bcl-2 cells because of the delay in apoptosis that unmasked p53-induced G1 growth arrest. This finding was further corroborated at the molecular level by analysis of the expression and function of key cell cycle regulatory genes in M1p53 versus M1p53/bcl-2 cells after the activation of wt p53 function; events that take place at early times during the p53-induced G1 arrest occur in both the M1p53 and the M1p53/bcl-2 cells, whereas later events occur only in the M1p53/bcl-2 cells, which undergo delayed apoptosis, thereby allowing the cells to complete G1 arrest. Finally, it was observed that a spectrum of p53 target genes implicated in p53-induced growth suppression and apoptosis were similarly regulated, either induced (gadd45, waf1, mdm2, and bax) or suppressed (c-myc and bcl-2), after activation of wt p53 function in M1p53 and M1p53/bcl-2 cells. Taken together, these findings show that wt p53 can simultaneously induce the genetic programs of both G1 growth arrest and apoptosis within the same cell type, in which the genetic program of cell death can proceed in either G1-arrested (M1p53/bcl-2) or cycling (M1p53) cells. These findings increase our understanding of the functions of p53 as a tumor suppressor and how alterations in these functions could contribute to malignancy.
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PMID:Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest. 774 28

mdm2 (mouse double minute) protein seems lead to p53 inactivation and therefore might potentially play a role in carcinogenesis. We have studied mdm2 gene amplification from 239 primary breast cancer tissues. mdm2 gene was amplified in 10% of cases (25/239). mdm2 amplification was associated with c-erbB2 amplification (P < 10(-3)). No other correlation was found. However there was inverse correlation between c-erbB2 gene amplification and hormonal receptors (P < 10(-4)), only from patients without mdm2 gene amplification.
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PMID:[Study of mdm2 gene amplification in primary breast tumors]. 774

The tumour suppressor protein p53 normally functions as a tetramer in a defined conformational state. Mutations within p53 which contribute to cancer development frequently induce a conformational shift in the protein which correlates with loss of wild type growth suppressor functions. Both the cell encoded mdm2 protein and the human papillomavirus oncoprotein E6 can regulate p53 function and we have examined the interaction of these proteins with p53. The E6/p53 association is sensitive to conformational alterations in the p53 protein, although oligomerisation is not necessary for this interaction to occur. Analysis of C-terminal p53 truncations has indicated that the region between residues 327 and 347 may play a role in E6 binding. Since monomeric forms of p53 retain transcriptional and transformation suppressor activities, our results indicate that E6 targets p53 proteins which retain these wild type functions. Conversely, the interaction of p53 with mdm2 is not dependent on the conformation of the p53 protein but is significantly impaired by loss of quaternary structure. It is possible that mdm2 plays a role in mediating activities of p53 which, unlike transcriptional activation, depend on oligomerisation.
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PMID:Oligomerisation of full length p53 contributes to the interaction with mdm2 but not HPV E6. 775 47

To investigate functions of wild type p53 in human cells, we introduced a (Ala-->Val) mutation at the 138th codon of the human p53 (Val138), which corresponds to the Val135 mutation of the temperature sensitive mouse p53. The human Val138 mutant showed temperature-sensitive transformation of rat embryo fibroblasts (REFs) in collaboration assay with activated ras, and arrested cell proliferation of transformed clones in G1 at 32.5 degrees C. Transient CAT assay for transcriptional activation in human Saos2 cells revealed activity equivalent to that of wild type at 32.5 degrees C but undetectable at 37.5 degrees C. These results suggest that the human Val138 mutant also exhibited the wild type phenotype at the permissive temperature as is for the mouse Val135 mutant, although we observed differences between the two mutants such as in transactivational activities in CV-1 and HeLa cells. Further, the role of cip1/waf1/sdi1 in the cell growth arrest of the Val138/ras-transformed REFs and Val138-introduced Saos2 cells was studied by northern hybridization analysis. Although rapid induction of cip1/waf1/sdi1 mRNA was observed in the Saos2 cells, no detectable induction of mRNAs for cip1/waf1/sdi1 and gadd45 was observed in the transformed REFs upon temperature shift-down, while mdm2 mRNA was enhanced, suggesting that the p53 gene could arrest cell growth by a mechanism other than that with induced expression of the gene for p21 cdk-cycline inhibitor.
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PMID:A temperature sensitive mutant of the human p53, Val138, arrests rat cell growth without induced expression of cip1/waf1/sdi1 after temperature shift-down. 776 Oct 89

Induction of apoptosis in tumor cells is an important mechanism of chemotherapy-induced cell death. The tumor-suppressor gene p53 is required for the efficient activation of apoptosis following chemotherapy. However, the molecular mechanism regulating p53-associated apoptosis remains controversial. In this study, we show that the expression of both wild-type p53 and MDM2 (murine double minute 2) proteins was induced when cis-diamminedichloroplatinum (cisplatin) caused apoptosis in human glioblastoma U87-MG cells, which expressed neither wild-type p53 nor MDM2 protein prior to treatment. Overexpression of MDM2 in U87-MG cells transfected with human mdm2 expression vector conferred the resistance of tumor cell to cisplatin-induced apoptosis. In contrast, the treatment with mdm2 antisense oligonucleotide targeted against mdm2 mRNA increased the susceptibility of tumor cells to apoptosis. Changes in expression level of MDM2 protein, however, did not affect the expression of wild-type p53 protein. These findings suggest that MDM2 protein may act as a negative regulator of cisplatin-induced apoptosis, and moreover, may play an important role in the development of resistance to cisplatin in human tumors.
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PMID:MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. 776 Nov

Pancreatic ductal adenocarcinomas induced in the Syrian golden hamster (SGH) by N-nitrosobis(2-oxopropyl)amine share many similarities with the human disease, including mutations of the K-ras oncogene. In vitro carcinogenesis studies with immortal SGH pancreatic duct cells indicate that neoplastic transformation in this system can occur without mutational inactivation of p53 suppressor gene. In this study we extend the genetic analysis of the in vivo SGH model to increase the number of cases analyzed for the status of K-ras and to determine further the spectrum of alterations involved; we have studied the status of the p53, DCC, and Rb-1 suppressor genes and the status of the mdm2 oncogene, which can involve p53 indirectly. The partial SGH-coding sequence of mdm2 and DCC was determined. K-ras mutation in the second position of codon 12 was present in 17 of 19 (90%) of tumors. Immunohistochemistry and single strand conformation polymorphism analysis showed no evidence of p53 mutation in 21 tumors. RNase protection assays showed overexpression of mdm2 in 5 of 19 (26%) tumors. Semiquantitative reverse transcription-PCR analysis showed a complete or partial loss of DCC expression in 10 of 19 (53%) neoplasms and of Rb-1 (42%) expression in 8 of 19 tumors when compared to matched controls. Deregulation of these genes appears to be significant in SGH pancreatic carcinogenesis as indicated by their frequencies. However, the fact that 6 tumors showed either only a K-ras mutation or the absence of alterations of the 5 genes analyzed indicates that additional as yet unstudied or unknown genes are also involved in SGH pancreatic duct carcinogenesis.
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PMID:Multiple genetic alterations in hamster pancreatic ductal adenocarcinomas. 778 Sep 69


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