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)

Cell cycle checkpoints can enhance cell survival and limit mutagenic events following DNA damage. Primary murine fibroblasts became deficient in a G1 checkpoint activated by ionizing radiation (IR) when both wild-type p53 alleles were disrupted. In addition, cells from patients with the radiosensitive, cancer-prone disease ataxia-telangiectasia (AT) lacked the IR-induced increase in p53 protein levels seen in normal cells. Finally, IR induction of the human GADD45 gene, an induction that is also defective in AT cells, was dependent on wild-type p53 function. Wild-type but not mutant p53 bound strongly to a conserved element in the GADD45 gene, and a p53-containing nuclear factor, which bound this element, was detected in extracts from irradiated cells. Thus, we identified three participants (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.
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PMID:A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. 142 16

The inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to ionising radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irradiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by ionising radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
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PMID:The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. 747 67

Incubating human cells in diethylmaleate (DEM) depletes the intracellular pool of reduced glutathione (GSH) and increases the concentration of oxidative free radicals. We found that DEM-induced oxidative stress reduced the ability of p53 to bind its consensus recognition sequence and to activate transcription of a p53-specific reporter gene. Nevertheless, DEM treatment induced expression of WAF1/CIP1 but not GADD45 mRNA. The fact that N-acetylcysteine, a precursor of GSH that blocks oxidative stress, prevented WAF1/CIP1 induction by DEM suggests that WAF1/CIP1 induction probably was a consequence of the ability of DEM to reduce intracellular GSH levels. DEM induced WAF1/CIP1 expression in Saos-2 and T98G cells, both of which lack functional p53 protein. DEM treatment did not produce an increase in membrane-associated protein kinase C, but ERK2, a mitogen-activated protein kinase, was phosphorylated in a manner consistent with ERK2 activation. DEM treatment also produced a dose-dependent delay in cell cycle progression, which at low concentrations (0.25 mM) consisted of a G2/M arrest and at higher concentrations (1 mM) also involved G1 and S phase delays. Our results indicate that oxidative stress induces WAF1/CIP1 expression and arrests cell cycle progression through a mechanism that is independent of p53. This mechanism may provide for cell cycle checkpoint control under conditions that inactivate p53.
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PMID:A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. 749 74

Transcriptional activation of target genes represents an important component of the tumour-suppressor function of p53 and provides a functional link between p53 and various growth-regulatory processes, including cell cycle progression (p21/WAF1), DNA repair (GADD45) and apoptosis (bax). Here we use a differential cloning approach to identify the gene encoding insulin-like growth factor binding protein 3 (IGF-BP3) as a novel p53-regulated target gene. Induction of IGF-BP3 gene expression by wild-type but not mutant p53 is associated with enhanced secretion of an active form of IGF-BP3 capable of inhibiting mitogenic signalling by the insulin-like growth factor IGF-1. Our results indicate that IGF-BP3 may link p53 to potential novel autocrine/paracrine signalling pathways and to processes regulated by or dependent on IGF(s), such as cellular growth, transformation and survival.
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PMID:Induction of the growth inhibitor IGF-binding protein 3 by p53. 756 79

The tumor suppressor protein p53 is intimately involved in the cellular response to DNA damage, controlling cell cycle arrest, apoptosis and the transcriptional induction of DNA damage inducible genes. A transcriptional target of p53, Gadd45, was recently found to bind to PCNA, a component of DNA replication/repair complexes, thereby implicating Gadd45 in DNA metabolism. Using biochemical assays, a role for Gadd45 in excision repair in vitro has been demonstrated. Antisense experiments have also indicated an in vivo role for the GADD45 gene in UV-irradiation survival. These discoveries establish a link between p53 and DNA repair through Gadd45.
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PMID:Stopped for repairs. 757 96

A human p53 mutant, p53Val-138 (amino acid 138, Alanine-->Valine), generated by in vitro mutagenesis was introduced into Saos-2 human osteosarcoma and Jurkat acute T-lymphoblastic leukemia cell lines, both lacking p53 protein expression. p53Val-138 caused growth arrest in Saos-2 cell line and apoptosis in Jurkat cell line at 32.5 degrees C while it allowed both cell lines to grow continuously at 37.5 degrees C. p53Val-138 activated expression of p53-responsive genes including MDM2, GADD45 and WAF1/CIP1/SD11 in Saos-2 cell line upon the temperature shift-down from 37.5 degrees C to 32.5 degrees C. Thus, p53Val-138 acted as a temperature-sensitive p53 mutant. Taking advantage of these human cell systems, we demonstrated that p53-mediated cell cycle arrest occurred in G1 and G2/M phases of Saos-2 cell line but not in Jurkat cell line. The induced level of WAF1/CIP1/SDI1 mRNA by p53 was extremely lower in Jurkat cell line than that of Saos-2 cell line. However, MDM2 mRNA accumulated to the similar levels in these two cell lines. These results suggest that a factor(s) other than p53 may be involved in differential expression of WAF1/CIP1/SDI1 and MDM2 mRNA.
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PMID:A human temperature-sensitive p53 mutant p53Val-138: modulation of the cell cycle, viability and expression of p53-responsive genes. 762 16

To investigate the relevance of the C-terminal domains of the human p53 tumor suppressor gene to its growth suppressive and transcriptional regulatory properties deletion mutants were generated which eliminated 30 (p53 delta 363), 60 (p53 delta 333) and 87 (p53 delta 306) amino acids from the C-terminus of the p53 protein. p53 delta 363 has lost the highly basic tail of the protein (residues 360-386). p53 delta 333 and p53 delta 306 lack the oligomerization domain (residues 320-360); p53 delta 306 has also lost the major nuclear localization signal of p53 (NLSI, residues 316-325). These mutants were assayed for transactivation from two p53 consensus binding sites and for transcriptional repression of two promoter systems in Calu6 lung cancer cells (p53 null). Moreover, their ability to inhibit cell growth in tumor cell lines with a defined p53 status was analysed. Deletion of the oligomerization domain correlated with significant loss of: (a) transactivation from a genomic sequence; (b) transcriptional repression; (c) the ability to inhibit colony formation. An intact NLSI was not a prerequisite for transactivation. p53 delta 363 behaved similarly to wt p53 in all the assays. We established an inducible expression system for p53 delta 363 in a human fibrosarcoma cell line known to be growth-suppressed by wt p53. The induction of p53 delta 363 expression also inhibited cell proliferation albeit to a lesser extent than wt p53. However, p53 delta 363 could upregulate WAF1/CIP1, GADD45 and MDM2 genes. Thus, the basis tail of p53 appears not to be required for the biological functions of the protein assayed.
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PMID:The basic carboxy-terminal domain of human p53 is dispensable for both transcriptional regulation and inhibition of tumor cell growth. 762 48

The cytotoxicity of Doxorubicin and cis-dichloro-diammine-platinum (DDP) was evaluated in clones, obtained from a human ovarian cancer cell line transfected with a temperature-sensitive p53 mutant, which express mutant p53 at 37 degrees C and wild-type-like p53 at 32 degrees C. DDP was equally active in cells not expressing p53 (SKN) or cells expressing a mutated form of p53 (SK23a kept at 37 degrees C) or a wild-type-like form of p53 (SK23a cells kept at 32 degrees C). In contrast, Doxorubicin was less cytotoxic in cells expressing wild-type p53 than in cells expressing no p53 or mutated p53. This reduction was not due to a decreased intracellular accumulation or to a faster efflux of Doxorubicin. Topoisomerase II was found to be present in the same amount in all the systems utilized and to be functionally active, thus not accounting for the observed effect of Doxorubicin. A clear induction of WAF1/CIP1 and GADD45 genes in cells expressing wild-type p53 after Doxorubicin treatment was found. DDP, which was equally active in the cells utilized, caused an increase in the transcription only of GADD45 gene but not of WAF1/CIP1 gene. Doxorubicin was also able to induce the transcription of WAF1/CIP1 gene in SKN cells (not expressing p53) or in SK23a cells at 37 degrees C (expressing mutated p53), indicating that the expression of this gene also, in some tumor-cell lines, is not necessarily or uniquely induced by wild-type p53.
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PMID:Decreased cytotoxic effects of doxorubicin in a human ovarian cancer-cell line expressing wild-type p53 and WAF1/CIP1 genes. 772 53

We investigated the sensitivity and sequential events that take place in thyroid epithelial cells after irradiation. Cell survival ratios at a dose of 2 Gy were 18 +/- 2.5%, 58 +/- 1.0%, 59 +/- 1.5%, and 98 +/- 1.8% in primary thyroid cells, papillary thyroid carcinoma cells, follicular thyroid carcinoma cells, and anaplastic thyroid carcinoma cells, respectively. Thyroid carcinoma cell lines carrying mutations in the p53 gene were resistant to ionizing radiation. Although irradiated cells were accumulated at G1 in primary thyroid cells even after low-dose irradiation (0.2 Gy), this phenomenon was not observed in the thyroid carcinoma cell lines. Wild-type p53 expression in primary thyroid cell was increased following irradiation, but mutated p53 in the thyroid carcinoma cell lines was unchanged. To clarify the signal transduction in the G1 arrest following irradiation, levels of expression of the p53 putative downstream effectors GADD45 and WAF1/Cip1 were examined. Despite the consistent level of GADD45 mRNA, the level of WAF1/Cip1 transcripts was increased in a radiation dose-dependent manner in primary thyroid cells. This increase in the WAF1/Cip1 mRNA level was observed 30 min after irradiation and continued for at least 48 h. A mobility shift assay performed using the sequence of the putative p53 DNA binding site on the WAF1/Cip1 and GADD45 genes as a probe showed that nuclear protein extracted from primary thyroid cells, anti-p53 antibody, and probe oligonucleotide-bound complex was clearly shifted. An increase in binding activity of the p53/antibody/DNA complex was observed following irradiation. In contrast, the nuclear extract from thyroid carcinoma cells could not bind the specific DNA site, suggesting that mutant p53 has lost its binding ability. Actinomycin D inhibited WAF1/Cip1 and GADD45 mRNA levels and cycloheximide stimulated up-regulation of both basal mRNA levels, but an additional increase of the mRNA expression following irradiation was observed only in the WAF1/Cip1 gene. These data suggest that p53 in postradiation acts at a transcriptional level on WAF1/Cip1 gene expression and that de novo protein synthesis is not required for this effect. These results suggest that the p53-WAF1/Cip1 pathway may play a central role in induction of G1 arrest following irradiation in human thyroid epithelial cells.
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PMID:Radiation-induced G1 arrest is selectively mediated by the p53-WAF1/Cip1 pathway in human thyroid cells. 774 5

We investigated temporal relationships between ionizing radiation-induced G1 arrest and induction of the p53-regulated genes GADD45, CIP1/WAF1, and MDM2 in a series of Burkitt's lymphoma and lymphoblastoid cell lines that differed in p53 gene status. Emphasis was placed on characterization of the EW36 cell line, which despite expressing wild-type p53 genes, is defective in G1 arrest following gamma-irradiation (P. M. O'Connor et al., Cancer Res., 53: 4776-4780, 1993). Induction of CIP1/WAF1, GADD45, and to a lesser extent MDM2 mRNA was observed in all wild-type p53 lines that arrested in G1. Cell lines that contained only mutant p53 genes or were heterozygous for p53 mutations failed to induce appreciable levels of these p53-regulated transcripts and did not arrest in G1. G1 arrest in the wild-type p53 cell line WMN was more prolonged than elevation of CIP1/WAF1, GADD45, or MDM2 transcripts, suggesting that G1 arrest duration must be dependent upon stability of these newly synthesized proteins. In agreement, we found that p21Cip1/Waf1, a potent inhibitor of G1-S phase cyclin-dependent kinases, was maintained at elevated levels throughout the period that WMN cells remained arrested in G1. EW36 cells exhibited normal induction of CIP1/WAF1, GADD45, and MDM2 mRNA following gamma-irradiation, suggesting that the defect in G1 arrest must reside downstream of p53 transactivation. Investigations into the stability of p53 and p21Cip1/Waf1 revealed that EW36 cells failed to maintain elevated levels of these proteins following irradiation. p53 levels decreased within 4 h of irradiation, and p21Cip1/Waf1 levels decreased shortly after the normal decline of CIP1/WAF1 mRNA levels. Degradation of p21Cip1/Waf1 coincided with the escape of EW36 cells from G1 arrest. Our studies suggest that p21Cip1/Waf1 stability may determine G1 arrest duration and that premature degradation of this protein could provide an alternative route to subversion of the G1 checkpoint in cancer cells.
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PMID:Relationships between G1 arrest and stability of the p53 and p21Cip1/Waf1 proteins following gamma-irradiation of human lymphoma cells. 775 91


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