Browsing by Author "Kochhar, Amit"

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    p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling
    (American Association for Cancer Research, 2014-06) Kochhar, Amit; Kopelovich, Levy; Sue, Erika; Guttenplan, Joseph B.; Herbert, Brittney-Shea; Dannenberg, Andrew J.; Subbaramaiah, Kotha; Department of Medical and Molecular Genetics, IU School of Medicine
    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.
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    Retraction: p53 Modulates Hsp90 ATPase Activity and Regulates Aryl Hydrocarbon Receptor Signaling
    (American Association for Cancer Research, 2022) Kochhar, Amit; Kopelovich, Levy; Sue, Erika; Guttenplan, Joseph B.; Herbert, Brittney-Shea; Dannenberg, Andrew J.; Subbaramaiah, Kotha; Medical and Molecular Genetics, School of Medicine
    This retracts the article "p53 Modulates Hsp90 ATPase Activity and Regulates Aryl Hydrocarbon Receptor Signaling" in Cancer Prev Res (Phila), volume 7 on page 596. This article (1) has been retracted at the request of the authors. There was evidence of data falsification or fabrication found in one figure. Suspicious duplications of band images were found in Fig. 5. A copy of this Retraction Notice was sent to the last known e-mail addresses for the 7 authors. Four authors (Levy Kopelovich, Brittney-Shea Herbert, Andrew J. Dannenberg, and Kotha Subbaramaiah) agreed to the retraction; three authors (Amit Kochhar, Erika Sue, and Joseph B. Guttenplan) did not respond. The authors apologize to the scientific community and deeply regret any inconveniences or challenges resulting from the publication and subsequent retraction of this article.