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J. Biol. Chem., Vol. 282, Issue 43, 31289-31301, October 26, 2007

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Cytosolic Accumulation of HSP60 during Apoptosis with or without Apparent Mitochondrial Release

EVIDENCE THAT ITS PRO-APOPTOTIC OR PRO-SURVIVAL FUNCTIONS INVOLVE DIFFERENTIAL INTERACTIONS WITH CASPASE-3^*

Dhyan Chandra¹², Grace Choy¹³, and Dean G. Tang⁴

From the Department of Carcinogenesis, the University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957 and the Program in Environmental and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, Houston, Texas 77030

Most heat shock proteins (HSPs) have pro-survival functions. However, the role of HSP60, a mitochondrial matrix protein, is somewhat controversial with both pro-survival and pro-apoptotic functions reported. Here we show that in numerous apoptotic systems HSP60 protein accumulates in the cytosol. In BMD188-induced cell death, HSP60 accumulates in the cytosol with significant mitochondrial release. In contrast, in apoptosis induced by multiple other inducers, the cytosolic HSP60 accumulates without an apparent mitochondrial release. The short interfering RNA-mediated knockdown experiments revealed that in BMD188-induced apoptosis, HSP60 has a pro-death function and that the pro-death role of HSP60 seems to involve caspase-3 maturation and activation in the cytosol. In contrast, HSP60 appears to play a pro-survival role in other apoptotic systems where there is no apparent mitochondrial release as its knockdown promotes cell death. In these latter apoptotic systems HSP60 does not associate with active caspase-3. In both cases, HSP60 does not appreciably interact with Bax. Taken together, our results suggest the following: 1) cytosolic accumulation of HSP60 represents a common phenomenon during apoptosis induction; 2) cytosolic HSP60 accumulation during apoptosis occurs either with or without apparent mitochondrial release; and 3) the cytosolically accumulated HSP60 possesses either pro-survival or pro-death functions, which involves differential interactions with caspase-3.

Received for publication, April 2, 2007 , and in revised form, August 15, 2007.

^* This work was supported in part by National Institutes of Health Grants AG023374 and ES15888, American Cancer Society Grant RSG MGO-105961, Department of Defense Grant W81XWH-07-1-0616 (to D. G. T.), and by NIEHS Center Grant ES07784 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² Supported by a National Institutes of Health K01 Award CA123142. Present address: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, NY 14263.

³ Supported by a Department of Defense Postdoctoral Traineeship Award W81XWH-04-1-0809. Present address: University of Texas, College of Natural Sciences, 1 University Station G2500, Austin, TX 78712.

⁴ To whom correspondence should be addressed: Dept. of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P. O. Box 389, 1808 Park Rd. 1-C, Smithville, TX 78957. Tel.: 512-237-9575; Fax: 512-237-2475; E-mail: dtang{at}mdanderson.org.

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