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p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kochhar, Amit Kopelovich, Levy Sue, Erika Guttenplan, Joseph B. Herbert, Brittney-Shea Dannenberg, Andrew J. Subbaramaiah, Kotha
Description	Author Affiliation: Kochhar A ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College); Kopelovich L ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College); Sue E ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College); Guttenplan JB ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College); Herbert BS ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College); Dannenberg AJ ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College); Subbaramaiah K ( Authors' Affiliations: Department of Medicine, Weill Cornell Medical College)
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.
File Format	HTM / HTML
ISSN	19406207
e-ISSN	19406215
DOI	10.1158/1940-6207.CAPR-14-0051
Journal	Cancer Prevention Research
Issue Number	6
Volume Number	7
Language	English
Publisher	American Association for Cancer Research
Publisher Date	2014-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Oncology Hsp90 Heat-shock Proteins Metabolism Receptors, Aryl Hydrocarbon Genetics Tumor Suppressor Protein P53 Physiology Adenosine Triphosphatases Cell Transformation, Neoplastic Cells, Cultured Cytochrome P-450 Cyp1a1 Cytochrome P-450 Cyp1b1 Enzyme Activation Gene Expression Regulation Polycyclic Hydrocarbons, Aromatic Protein Transport Signal Transduction Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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