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p34^SEI-1 Inhibits Apoptosis through the Stabilization of the X-Linked Inhibitor of Apoptosis Protein: p34^SEI-1 as a Novel Target for Anti–Breast Cancer Strategies

¹ Research Center for Women's Diseases, Division of Biological Sciences, Sookmyung Women's University, ² Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, ³ Department of Pathology, Catholic of University College of Medicine, ⁴ Division of radiation cancer biology, Korea institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, 139-706, ⁵ Department of Microbial Engineering, Konkuk University, and ⁶ Department of Basic Science of Oriental Medicine, Laboratory of Clinical Biology and Pharmacogenomics Institute of Oriental Medicine, Kyunghee University, Seoul, Korea; and ⁷ Department of Biological Sciences, Myongji University, San38-2 Namdong, cheoin-gu, Youngin, Gyeonggido, Korea

Requests for reprints: Dong-Hoon Jin, Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Korea. Phone: 82-2-740-8216; E-mail: inno183{at}sm.ac.kr, inno183{at}snu.ac.kr and Myeong-Sok Lee, Division of Biological Sciences, Sookmyung Women's University, Seoul, Korea. Phone: 82-2-2077-9418; Fax: 82-2-741-8208; E-mail: mslee{at}sookmyung.ac.kr.

Key Words: P34^SEI-1 • XIAP • apoptosis • ubiquitination

The p34^SEI-1 protein exerts oncogenic effects via regulation of the cell cycle, which occurs through a direct interaction with cyclin-dependent kinase 4. Such regulation can increase the survival of various types of tumor cells. Here, we show that the antiapoptotic function of p34^SEI-1 increases tumor cell survival by protecting the X-linked inhibitor of apoptosis protein (XIAP) from degradation. Our findings show that p34^SEI-1 inhibits apoptosis. This antiapoptotic effect was eliminated by the suppression of p34^SEI-1 expression. We also determined that direct binding of p34^SEI-1 to the BIR2 domain prevents ubiquitination of XIAP. Interestingly, p34^SEI-1 expression is absent or weak in normal tissues but is strongly expressed in tissues obtained from patients with breast cancer. Furthermore, the expression levels of p34^SEI-1 and XIAP seem to be coordinated in human breast cancer cell lines and tumor tissues. Thus, our findings reveal that p34^SEI-1 uses a novel apoptosis-inhibiting mechanism to stabilize XIAP. [Cancer Res 2009;69(3):741–6]