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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1736    most recent ajpheart.91507.2007v2 ajpheart.91507.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Venkatakrishnan, C. D. Articles by Ilangovan, G. Search for Related Content PubMed PubMed Citation Articles by Venkatakrishnan, C. D. Articles by Ilangovan, G.

HSP27 regulates p53 transcriptional activity in doxorubicin-treated fibroblasts and cardiac H9c2 cells: p21 upregulation and G₂/M phase cell cycle arrest

¹Division of Cardiovascular Medicine, Department of Internal Medicine, ³Department of Surgery, Davis Heart and Lung Research Institute, ⁴Department of Radiation, The Ohio State University, Columbus; and ²Division of Critical Care Medicine, Cincinnati Children's Hospital and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 20 December 2007 ; accepted in final form 4 February 2008

Treatment of cancer patients with anthracyclin-based chemotherapeutic drugs induces congestive heart failure by a mechanism involving p53. However, it is not known how p53 aggravates doxorubicin (Dox)-induced toxicity in the heart. On the basis of in vitro acute toxicity assay using heat shock factor-1 (HSF-1) wild-type (HSF-1^+/+) and HSF-1-knockout (HSF-1^–/–) mouse embryonic fibroblasts and neonatal rat cardiomyocyte-derived H9c2 cells, we demonstrate a novel mechanism whereby heat shock protein 27 (HSP27) regulates transcriptional activity of p53 in Dox-treated cells. Inhibition of p53 by pifithrin- (PFT-) provided different levels of protection from Dox that correlate with HSP27 levels in these cells. In HSF-1^+/+ cells, PFT- attenuated Dox-induced toxicity. However, in HSF-1^–/– cells (which express a very low level of HSP27 compared with HSF-1^+/+ cells), there was no such attenuation, indicating an important role of HSP27 in p53-dependent cell death. On the other hand, immunoprecipitation of p53 was found to coimmunoprecipitate HSP27 and vice versa (confirmed by Western blotting and matrix-assisted laser desorption/ionization time of flight), demonstrating HSP27 binding to p53 in Dox-treated cells. Moreover, upregulation of p21 was observed in HSF-1^+/+ and H9c2 cells, indicating that HSP27 binding transactivates p53 and enhances transcription of p21 in response to Dox treatment. Further analysis with flow cytometry showed that increased expression of p21 results in G₂/M phase cell cycle arrest in Dox-treated cells. Overall, HSP27 binding to p53 attenuated the cellular toxicity by upregulating p21 and prevented cell death.

redox signaling; DNA repair; cell survival; oxidative stress

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