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)

In this study we describe a novel putative p53-responsive gene, designated p22/PACAP response gene 1 (PRG1), recently identified as a proliferation-associated early-response gene in rats. By means of electrophoretic mobility shift assay and CAT-reporter gene assay, we could demonstrate that the p53 binding site residing in the promoter of p22/PRG1 is functional in vitro. Furthermore, in clone 6 cells expression of p22/PRG1 is induced in parallel to p21/Waf1 under conditions permitting mutant p53 to adopt wild-type configuration. An increase of p22/PRG1 transcription was also observed in gamma-irradiated rat splenocytes, which undergo p53-dependent apoptosis. Our findings demonstrate that p22/PRG1 fulfills all essential criteria as a p53 target gene and might be implicated in p53-dependent apoptosis.
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PMID:p22/PACAP response gene 1 (PRG1): a putative target gene for the tumor suppressor p53. 992 93

Metallocene complexes containing vanadium induce apoptosis in human cancer cells by an as yet unknown mechanism and may therefore be useful as a new class of cytotoxic anticancer drugs. Ultrastructural studies showing the formation of metallocene-DNA complexes prompted the hypothesis that their mechanism of action may resemble the DNA damage induced by cisplatin. Molecular genotoxicity testing provides insights into the mechanisms of action of new chemotherapeutic agents. Therefore, we determined the effects of three cytotoxic vanadocene complexes, vanadocene dichloride, vanadocene dithiocyanate, and vanadocene dioxycyanate, on genomic stability using the yeast DEL recombination assay and transcriptional activation of genotoxic stress-specific promoters in human HepG2 cells using the CAT-Tox(L) assay. Cisplatin caused an 11-fold increase of recombination frequency in yeast and induced transcriptional activation of the DNA damage-associated promoters such as the minimum promoter containing p53 response elements and the GADD45 promoter in addition to activating the promoters for c-fos, heat shock protein 70, metallothionine IIa, and the minimum promoter containing nuclear factor kappa(kappa)B response elements. In contrast to cisplatin, vanadocene complexes did not increase the DEL recombination frequency in yeast nor did they activate any of the DNA damage-associated promoters in HepG2 cells. Vanadocene complexes triggered activation of the c-fos promoter without affecting the minimum promoter containing p53 response elements or the GADD45 promoter. These results indicate that the apoptotic signal of vanadocene complexes is not triggered by primary DNA damage and it does not require p53 induction, thereby disproving the hypothesis that it mechanistically resembles the cytotoxic action of cisplatin.
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PMID:Molecular genotoxicity profiles of apoptosis-inducing vanadocene complexes. 993 Dec 82

Synergism between exposure to chemical carcinogens and infection with the hepatitis B virus (HBV) has been implicated in the high incidence of hepatocellular carcinoma. In this study we report that the HBV protein HBx, inhibits cellular DNA repair capacity in a p53-independent manner. Two alternative assays were used: the host cell reactivation assay, which measures the cell's capacity to repair DNA damage in a reporter plasmid, and unscheduled DNA synthesis, which measures the overall DNA repair capacity in damaged cells. Two p53-proficient cell lines, the hepatocellular carcinoma cell line HepG2 and liver epithelial cell line CCL13, were co-transfected with the pCMV-HBx reporter plasmid and the pCMV-CAT plasmid damaged with UVC radiation. Compared with cells transfected with control plasmid, the presence of HBx resulted in approximately 50% inhibition of the cell's capacity to reactivate CAT activity of UVC-damaged plasmid, and approximately 25% inhibition of unscheduled DNA synthesis in cells treated with either aflatoxin B1 epoxide or UVC radiation. Using the p53-deficient cell line Saos-2, we demonstrated that expression of HBx also resulted in diminished overall cellular DNA repair of damage induced by both aflatoxin B1 epoxide and UVC radiation, using both the host cell reactivation and unscheduled DNA synthesis assays. In summary, this study provides evidence for p53-independent regulation of DNA repair by HBx.
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PMID:Downregulation of DNA excision repair by the hepatitis B virus-x protein occurs in p53-proficient and p53-deficient cells. 1019 May 65

We studied the tissue-specific expression of the p53 gene in different parts of the intestine of mice treated with low doses of a carcinogen and exposed to different p53 antibodies. The human p53 promoter-CAT transgenic mice were immunized with different p53 antibodies (monoclonal - PAb 421 and DO1, and polyclonal - H-p53 and anti-soluble p53 IgG) and then exposed to low doses of dimethylhydrazine (DMH). Enzymatic CAT activity was determined in the ileum and colon 8 weeks later after the final injection of DMH. Expression of the p53 transgene in the normal ileum was twice as high as in the colon. Treatment with DMH significantly decreased the expression of the p53 transgene both in the ileum (from 18% to 100%) and in the colon (from 10% to 52%). Vaccination of mice protected at least in part such a decrease. The most effective results were found after exposure of mice to polyclonal H-p53 and to a lesser extent to anti-p53 IgG. No difference was found in the effects of antibodies on the small and large intestines. We concluded that polyclonal antibodies were more effective than monoclonal ones in protection against anti-p53 action of DMH. The observation of these effects may make it possible to explain the higher antitumor activity of polyclonal antibodies.
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PMID:Tissue-specific expression of the p53 tumor-suppressor gene in the intestine of transgenic mice exposed to DMH and p53 antibodies. 1037 75

In Epstein-Barr virus (EBV)-associated tumors in nonimmunocompromised patients, EBV gene expression is highly restricted. EBV-encoded nuclear antigen (EBNA)-1 is expressed, whereas the immunogenic and proliferative EBNAs are not. This pattern of EBNA expression is generated by usage of the BamHI-Q promoter (Qp). We have determined that the JAK/STAT pathway positively regulates Qp activity. In transient-transfection assays, a Qp-CAT reporter was activated by cotransfected JAK-1 and by treatment of cells with the cytokine IL-6. The ability of Qp to bind signal transducer and activator of transcription (STAT) proteins was directly demonstrated by electrophoretic mobility-shift assay, and mutation of potential STAT-binding sites reduced Qp responsiveness to Janus kinase (JAK)-1. Consistent with a role for STATs in Qp function, Qp using Burkitt's lymphoma Rael cells and cultured nasopharyngeal carcinoma (NPC) cells contained nuclear STAT protein. We investigated whether the inability to maintain EBV-positive NPC cell lines in culture was related to Qp activity. Passaging of the NPC cell line HK666 led to activation of expression of BZLF1, which encodes Zta and loss of Qp function. Transient expression assays linked Zta expression to the down-regulation of Qp. Cotransfection of Zta reduced Qp activity in reporter assays. This negative regulation required Zta DNA-binding activity. We provide evidence that Zta up-regulation of p53 leads to p53-mediated interference with JAK/STAT activation of Qp. The data imply that JAK/STAT signaling has a role in EBV-associated malignancies.
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PMID:The Epstein-Barr virus latency BamHI-Q promoter is positively regulated by STATs and Zta interference with JAK/STAT activation leads to loss of BamHI-Q promoter activity. 1043 Sep 44

The cell cycle inhibitor protein p21(WAF1/Cip1) (p21) is a critical downstream effector in p53-dependent mechanisms of growth control and p53-independent pathways of terminal differentiation. We have recently reported that the transforming growth factor-beta pathway-specific Smad3 and Smad4 proteins transactivate the human p21 promoter via a short proximal region, which contains multiple binding sites for the ubiquitous transcription factor Sp1. In the present study we show that the Sp1-occupied promoter region mediates transactivation of the p21 promoter by c-Jun and the related proteins JunB, JunD, and ATF-2. By using gel electrophoretic mobility shift assays we show that this region does not contain a binding site for c-Jun. In accordance with the DNA binding data, c-Jun was unable to transactivate the p21 promoter when overexpressed in the Sp1-deficient Drosophila-derived SL2 cells. Coexpression of c-Jun and Sp1 in these cells resulted in a strong synergistic transactivation of this promoter. In addition, a chimeric promoter consisting of six tandem high affinity Sp1-binding sites fused with the CAT gene was transactivated by overexpressed c-Jun in HepG2 cells. The above data propose functional cooperation between c-Jun and Sp1. Physical interactions between the two factors were demonstrated in vitro by using GST-Sp1 hybrid proteins expressed in bacteria and in vitro transcribed-translated c-Jun. The region of c-Jun mediating interaction with Sp1 was mapped within the basic region leucine zipper domain. In vivo, functional interactions between c-Jun and Sp1 were demonstrated using a GAL4-based transactivation assay. Overexpressed c-Jun transactivated a chimeric promoter consisting of five tandem GAL4-binding sites only when coexpressed with GAL4-Sp1-(83-778) fusion proteins in HepG2 cells. By utilizing the same assay, we found that the glutamine-rich segment of the B domain of Sp1 (Bc, amino acids 424-542) was sufficient for c-Jun-induced transactivation of the p21 promoter. In conclusion, our data support a mechanism of superactivation of Sp1 by c-Jun, which is based on physical and functional interactions between these two transcription factors on the human p21 and possibly other Sp1-dependent promoters.
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PMID:c-Jun transactivates the promoter of the human p21(WAF1/Cip1) gene by acting as a superactivator of the ubiquitous transcription factor Sp1. 1050 25

We have previously shown that ETS transcription factors, regulate cell growth and differentiation, and ETS1 and ETS2 are able to transcriptionally regulate wt p53 gene expression. In the present study we show that the ETS transcription factors also play a role in regulating expression of GADD153, a wt p53 inducible gene, which induces growth arrest and apoptosis in response to stress signals or DNA damage. We report the presence of a single EBS in the human GADD153 promoter, and that the GADD45 gene promoter lacks EBSs. The GADD153 promoter EBS shows a very high affinity for ETS1 and FLI-1 gene products. In addition, our data show that both ETS1 and FLI-1 strongly activate transcription of the GADD153 EBS linked to the CAT reporter gene. Our results also demonstrate how ETS1 and FLI-1 specifically regulate GADD153 expression. In addition, ectopic ETS2 protein expression resulted in only a weak induction of the same CAT reporter construct. The ETS1 and FLI-1 proteins provide a novel mechanism of activation for GADD153, allowing these two ETS genes to control its expression during cell growth and differentiation, rather than in response to oxidative stress.
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PMID:Regulation of the human stress response gene GADD153 expression: role of ETS1 and FLI-1 gene products. 1051 Apr 72

After the Chernobyl accident in 1986, there was a significant increase in the incidence of papillary thyroid carcinoma in fallout-exposed children from Belarus. We studied the p53 gene from 24 papillary thyroid carcinoma cases presenting in 1996. All subjects lived in contaminated regions of Belarus at the time of the accident and were under age 20 when exposed to fallout. Exons 5 through 9 of p53 were amplified from genomic tumor DNA using the polymerase chain reaction (PCR). The PCR products were analyzed by direct DNA sequencing using an automated sequencer. Five cases each exhibited two molecular alterations within exon 5. Alterations were confirmed by sequencing in both directions. One alteration, involving codon 167 (CAG-->CAT) in all five cases, resulted in the substitution of HIS for GLN. The second alteration, involving codon 183 (TCA-->TGA) in all five cases, resulted in a premature termination codon. Leukocyte DNA from each of the positive cases was analyzed and found to contain only wild-type p53 sequence. These results suggest that mutations involving codons 167 and 183 in the p53 locus are important in the pathogenesis of a subset (21%) of radiation-induced papillary thyroid carcinomas from Belarus.
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PMID:Molecular alterations involving p53 codons 167 and 183 in papillary thyroid carcinomas from chernobyl-contaminated regions of belarus. 1069 10

Recent data suggest that additional factors, other than UV radiation, are involved in the etiology of non-melanoma skin cancer. These include alterations in the tumor suppressor genes, p53, p16$L*I*U$LINK4a$L*I$L/CDKN2A, p21$L*I*U$LWAF1/CIP1$L*I$L and the PTCH gene, as well as cytokines. Papillomavirus infections have been implicated in the etiology of non-melanoma skin cancer. The interaction of tumor suppressor genes and cytokines with the oncoproteins of high-risk mucosal HPV types have been studied in detail, but very little is known about the cutaneous HPV types. We have studied the effect of UV radiation on the URRs of HPV 1, 2, 3, 5, 7, 20, 23, 27, 38, 41, and 77. Neither the CAT-expression and promoter activity of these HPV types, nor presence or absence of wild-type or mutated p53 in the cell lines used, could be related to the DNA sequence homology between the different HPV types or their biological behavior.
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PMID:Human papillomaviruses in non-melanoma skin cancer. 1071 88

The bradykinin type 2 receptor (BK2) is a developmentally regulated G protein-coupled receptor that mediates diverse actions such as vascular reactivity, salt and water excretion, inflammatory responses, and cell growth. However, little is known regarding regulation of the BK2 gene. We report here that the rat BK2 receptor is transcriptionally regulated by the tumor suppressor protein p53. The 5'-flanking region of the rat BK2 gene contains two p53-like binding sites: a sequence at -70 base pairs (P1 site) that is conserved in the murine and human BK2 genes; and a sequence at -707 (P2) that is not. The P1 and P2 motifs bind specifically to p53, as assessed by gel mobility shift assays. Transient transfection into HeLa cells of a CAT reporter construct driven by 1.2-kilobases of the BK2 gene 5'-flanking region demonstrated that the BK2 promoter is dose dependently activated by co-expression of wild-type p53. Co-expression of a dominant negative mutant p53 suppresses the activation of BK2 by wild-type p53. Promoter truncation localized the p53-responsive element to the region between -38 and -94 base pairs encompassing the p53-binding P1 sequence. Furthermore, p53-mediated activation of the BK2 promoter is augmented by the transcriptional co-activators, CBP/p300. Interestingly, removal of the P2 site by truncation or site-directed deletion amplifies p53-mediated activation of the BK2 promoter. These results demonstrate that the rat BK2 promoter is a target for p53-mediated activation and suggest a new physiological role for p53 in the regulation of G protein-coupled receptor gene expression.
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PMID:The bradykinin type 2 receptor is a target for p53-mediated transcriptional activation. 1074 62


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