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J. Biol. Chem., Vol. 282, Issue 46, 33284-33294, November 16, 2007

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Identification of a Novel Inhibitor of Differentiation-1 (ID-1) Binding Partner, Caveolin-1, and Its Role in Epithelial-Mesenchymal Transition and Resistance to Apoptosis in Prostate Cancer Cells^*

Xiaomeng Zhang, Ming-Tat Ling, Qi Wang, Chi-Keung Lau, Steve C. L. Leung, Terence K. Lee, Annie L. M. Cheung, Yong-Chuan Wong¹, and Xianghong Wang²

From the Cancer Biology Group, the Departments of Anatomy and Surgery, Faculty of Medicine, Pokfulam, University of Hong Kong, Hong Kong, Special Administrative Region, China

Recently, ID-1 (inhibitor of differentiation/DNA binding) is suggested as an oncogene and is reported to promote cell proliferation, invasion, and survival in several types of human cancer cells through multiple signaling pathways. However, how Id-1 interacts with these pathways and the immediate downstream effectors of the Id-1 protein are not known. In this study, using a yeast two-hybrid screening technique, we identified a novel Id-1-interacting protein, caveolin-1 (Cav-1), a cell membrane protein, and a positive regulator of cell survival and metastasis in prostate cancer. Using an immunoprecipitation method, we found that the helix-loop-helix domain of the Id-1 protein was essential for the physical interaction between Id-1 and Cav-1. In addition, we also demonstrated that the physical interaction between Id-1 and Cav-1 played a key role in the epithelial-mesenchymal transition and increased cell migration rate as well as resistance to taxol-induced apoptosis in prostate cancer cells. Furthermore, our results revealed that this effect was regulated by Id-1-induced Akt activation through promoting the binding activity between Cav-1 and protein phosphatase 2A. Our study demonstrates a novel Id-1 binding partner and suggests a molecular mechanism that mediates the function of Id-1 in promoting prostate cancer progression through activation of the Akt pathway leading to cancer cell invasion and resistance to anticancer drug-induced apoptosis.

Received for publication, June 21, 2007 , and in revised form, September 10, 2007.

^* This work was supported by the Association for International Cancer Research, UK (to X. W.), and Research Grants Council HKU7470/04M (to Y. C. W.). 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) NM_001753 [GenBank] .

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence may be addressed: Dept. of Anatomy, University of Hong Kong, 1/F, Faculty of Medicine Bldg., 21 Sassoon Rd., Hong Kong, China. Tel.: 852-2819-2868; Fax: 852-2817-0857; E-mail: ycwong{at}hkucc.hku.hk. ² To whom correspondence may be addressed: xhwang{at}hkucc.hku.hk.

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