title: p53 and ATM/ATR regulate 7,12-dimethylbenz[a]anthracene-induced immunosuppression.
abstract: 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.
authors.affiliation: College of Pharmacy, 1 University of New Mexico, MSC09 5360, Albuquerque, NM 87131, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.forename: Leah A
authors.initials: LA
authors.lastname: Mitchell
authors.forename: Fredine T
authors.initials: FT
authors.lastname: Lauer
authors.forename: Scott W
authors.initials: SW
authors.lastname: Burchiel
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D007107:Immune System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases