Browsing by Author "Dannenberg, Andrew J."

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    Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells
    (American Society for Biochemistry and Molecular Biology, 2016-07-29) Subbaramaiah, Kotha; Brown, Kristy A.; Zahid, Heba; Balmus, Gabriel; Weiss, Robert S.; Herbert, Brittney-Shea; Dannenberg, Andrew J.; Medical and Molecular Genetics, School of Medicine
    Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a co-chaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1α, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1α and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1α or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1α, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1α, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1α were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/HIF-1α axis mediates the induction of aromatase in LFS.
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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.