Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor protein p53 is a transcription factor that regulates apoptotic responses produced by genotoxic agents. Previous studies have reported that 7,12-dimethylbenz[a]anthracene (DMBA)-induced bone marrow toxicity is p53-dependent in vivo. Our laboratory has shown that DMBA-induced splenic immunosuppression is CYP1B1- and microsomal epoxide hydrolase (mEH)-dependent, demonstrating that the DMBA-3,4-dihydrodiol-1,2-epoxide metabolite (DMBA-DE) is probably responsible for DMBA-induced immunosuppression. DMBA-DE is known to bind to DNA leading to strand breaks. Therefore, we postulated that a p53 pathway is required for DBMA-induced immunosuppression. In the present studies, our data show that activated p53 accumulated in the nuclei of spleen cells in WT and AhR-null mice after DMBA treatment, but not in CYP1B1-null or mEH-null mice. These results suggest that DMBA activates p53 in a CYP1B1- and mEH-dependent manner in vivo but is not AhR-dependent. Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein (ATR) are sensors for DNA damage that signal p53 activation. Increased ATM, phospho-ATM (Ser(1987)), and ATR levels were observed after DMBA treatment in WT, p53-null, and AhR-null mice but not in CYP1B1-null or mEH-null mice. Therefore, ATM and ATR seem to act upstream of p53 as sensors of DNA damage. Ex vivo immune function studies demonstrated that DMBA-induced splenic immunosuppression is p53-dependent at doses of DMBA that produce immunosuppression in the absence of cytotoxicity. High-dose DMBA cytotoxicity may be associated with p53-independent pathways. This study provides new insights into the requirement of genotoxicity for DMBA-induced immunosuppression in vivo and highlights the roles of ATM/ATR in signaling p53.
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PMID:p53 and ATM/ATR regulate 7,12-dimethylbenz[a]anthracene-induced immunosuppression. 1792 58

7, 12- Dimethylbenz-(a)-anthracene (DMBA) has been used for a long time to induce rat mammary gland carcinogenesis. In a previous paper we described the effects of diet, of non-steroidal anti-inflammatory drugs and the combination of these two factors on breast cancer. We also pointed out that DMBA tumor generating process is still poorly understood. The present study attempts to explore whether P53 or the pro-apoptotic protein Bcl-2 are potential targets of DMBA in its induction of breast tumors in the Sprague-Dawley rat breast tumorigenesis model. Our results indicate that the DBMA-induced tumors are apparently the result of P53 inactivation. This inactivation results in tumorigenesis, probably aided by the absence of Bcl-2 in the tumor cells of the Sprague-Dawley rat animal model. We discuss the potential mechanisms by which P53 inactivation results in tumorigenesis.
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PMID:The role of P53 and Bcl-2 proteins in 7, 12-dimethylbenz-(a)-anthracene-induced tumor growth. 2202 60