p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling

Amit Kochhar, Levy Kopelovich, Erika Sue, Joseph B. Guttenplan, Brittney-Shea Herbert, Andrew J. Dannenberg, Kotha Subbaramaiah

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)596-606
Number of pages11
JournalCancer Prevention Research
Volume7
Issue number6
DOIs
StatePublished - 2014

Fingerprint

HSP90 Heat-Shock Proteins
Aryl Hydrocarbon Receptors
Cytochrome P-450 CYP1A1
Adenosine Triphosphatases
Polycyclic Aromatic Hydrocarbons
Benzo(a)pyrene
Carcinogenesis
Li-Fraumeni Syndrome
Gene Expression
DNA Adducts
Mutagens
Smoke
Tobacco
Proteins
Transcription Factors
Down-Regulation
Epithelial Cells
Ligands
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Kochhar, A., Kopelovich, L., Sue, E., Guttenplan, J. B., Herbert, B-S., Dannenberg, A. J., & Subbaramaiah, K. (2014). p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling. Cancer Prevention Research, 7(6), 596-606. https://doi.org/10.1158/1940-6207.CAPR-14-0051

p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling. / Kochhar, Amit; Kopelovich, Levy; Sue, Erika; Guttenplan, Joseph B.; Herbert, Brittney-Shea; Dannenberg, Andrew J.; Subbaramaiah, Kotha.

In: Cancer Prevention Research, Vol. 7, No. 6, 2014, p. 596-606.

Research output: Contribution to journalArticle

Kochhar, A, Kopelovich, L, Sue, E, Guttenplan, JB, Herbert, B-S, Dannenberg, AJ & Subbaramaiah, K 2014, 'p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling', Cancer Prevention Research, vol. 7, no. 6, pp. 596-606. https://doi.org/10.1158/1940-6207.CAPR-14-0051
Kochhar, Amit ; Kopelovich, Levy ; Sue, Erika ; Guttenplan, Joseph B. ; Herbert, Brittney-Shea ; Dannenberg, Andrew J. ; Subbaramaiah, Kotha. / p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling. In: Cancer Prevention Research. 2014 ; Vol. 7, No. 6. pp. 596-606.
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