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

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

^* To whom correspondence should be addressed. E-mail: inno183{at}sm.ac.kr.

	Abstract

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]

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