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J. Biol. Chem., Vol. 280, Issue 17, 16942-16948, April 29, 2005

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Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXR/Nur77^*

Kuk-Wha Lee, Liqun Ma, Xinmin Yan, Bingrong Liu, Xiao-kun Zhang, and Pinchas Cohen¶

From the Division of Pediatric Endocrinology, Mattel Children's Hospital at UCLA, David Geffen School of Medicine, Los Angeles, California 90095 and Cancer Center, The Burnham Institute, La Jolla, California 92037

Insulin-like growth factor-binding protein-3 (IGFBP-3) induces apoptosis by its ability to bind insulin-like growth factors (IGFs) as well as its IGF-independent effects involving binding to other molecules including the retinoid X receptor- (RXR). Here we describe that in response to IGFBP-3, the RXR binding partner nuclear receptor Nur77 rapidly undergoes translocation from the nucleus to the mitochondria, initiating an apoptotic cascade resulting in caspase activation within 6 h. This translocation is a type 1 IGF receptor-signaling independent event as IGFBP-3 induces Nur77 translocation in R-cells. IGFBP-3 and Nur77 are additive in inducing apoptosis. GFP-Nur77 transfection into RXR wild-type and knock-out mouse embryonic fibroblasts and subsequent treatment with IGFBP-3 show that RXR is required for IGFBP-3-induced Nur77 translocation and apoptosis. Addition of IGFBP-3 to 22RV1 cell lysates enhanced the ability of GST-RXR to "pull down" Nur77, and overexpression of IGFBP-3 enhanced the accumulation of mitochondrial RXR. This unique nongenotropic nuclear pathway supports an emerging role for IGFBP-3 as a novel, multicompartmental signaling molecule involved in induction of apoptosis in malignant cells.

Received for publication, November 11, 2004 , and in revised form, February 16, 2005.

^* This work was supported in part by a Prostate Cancer Foundation award and National Institutes of Health Grants RO1AG20954, P50CA92131, and RO1CA100938 (to P. C.), a fellowship award from the Giannini Foundation (to K.-W. L.), a grant from the Stein-Oppenheimer Foundation (to K.-W. L.), a grant from the Lawson Wilkins Pediatric Endocrinology Society (to K.-W. L.), and National Institutes of Health Grant 2K12HD34610 (to K.-W. L.). 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.

^¶ To whom correspondence should be addressed. Tel.: 310-206-5844; Fax: 310-206-5843; E-mail: hassy{at}mednet.ucla.edu.

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