title: p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling.
abstract: The aryl hydrocarbon receptor (AhR), a client protein of heat shock protein 90 (Hsp90), is a ligand-activated transcription factor that plays a role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis. Tobacco smoke activates AhR signaling leading to increased transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to mutagens. Recently, p53 was found to regulate Hsp90 ATPase activity via effects on activator of Hsp90 ATPase (Aha1). It is possible, therefore, that AhR-dependent expression of CYP1A1 and CYP1B1 might be affected by p53 status. The main objective of this study was to determine whether p53 modulated AhR-dependent gene expression and PAH metabolism. Here, we show that silencing p53 led to elevated Aha1 levels, increased Hsp90 ATPase activity, and enhanced CYP1A1 and CYP1B1 expression. Overexpression of wild-type p53 suppressed levels of CYP1A1 and CYP1B1. The significance of Aha1 in mediating these p53-dependent effects was determined. Silencing of Aha1 led to reduced Hsp90 ATPase activity and downregulation of CYP1A1 and CYP1B1. In contrast, overexpressing Aha1 was associated with increased Hsp90 ATPase activity and elevated levels of CYP1A1 and CYP1B1. Using p53 heterozygous mutant epithelial cells from patients with Li-Fraumeni syndrome, we show that monoallelic mutation of p53 was associated with elevated levels of CYP1A1 and CYP1B1 under both basal conditions and following treatment with benzo[a]pyrene. Treatment with CP-31398, a p53 rescue compound, suppressed benzo[a]pyrene-mediated induction of CYP1A1 and CYP1B1 and the formation of DNA adducts. Collectively, our results suggest that p53 affects AhR-dependent gene expression, PAH metabolism, and possibly carcinogenesis.
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IndianaAuthors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Amit
authors.initials: A
authors.lastname: Kochhar
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Erika
authors.initials: E
authors.lastname: Sue
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IndianaAuthors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Guttenplan
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Brittney-Shea
authors.initials: BS
authors.lastname: Herbert
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.affiliation: Authors' Affiliations: Department of Medicine, Weill Cornell Medical College; Department of Basic Sciences, College of Dentistry; and Department of Environmental Medicine, School of Medicine, New York University, New York; Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana ksubba@med.cornell.edu.
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000251:Adenosine Triphosphatases
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