한빛사논문
- 조회2,143
Abstract
Min-Goo Lee, Jikhyon Han, Seong-In Jeong, Nam-Gu Her, Jin-Hee Lee, Tae-Kyu Ha, Min-Ju Kang, Byung-Kyu Ryu, and Sung-Gil Chi1
Department of Life Sciences, Korea University, Seoul 136-701, Korea
Abstract
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a tumor suppressor that is frequently inactivated in many human cancers. However, the molecular mechanism underlying its growth-inhibitory function remains largely unknown. Here, we report that XAF1 forms a positive feedback loop with p53 and acts as a molecular switch in p53-mediated cell-fate decisions favoring apoptosis over cell-cycle arrest. XAF1 binds directly to the N-terminal proline-rich domain of p53 and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of p53. XAF1 stimulates homeodomain-interacting protein kinase 2 (HIPK2)-mediated Ser-46 phosphorylation of p53 by blocking E3 ubiquitin ligase Siah2 interaction with and ubiquitination of HIPK2. XAF1 also steps up the termination of p53-mediated cell-cycle arrest by activating zinc finger protein 313 (ZNF313), a p21WAF1-targeting ubiquitin E3 ligase. XAF1 interacts with p53, Siah2, and ZNF313 through the zinc finger domains 5, 6, and 7, respectively, and truncated XAF1 isoforms preferentially expressed in cancer cells fail to form a feedback loop with p53. Together, this study uncovers a novel role for XAF1 in p53 stress response, adding a new layer of complexity to the mechanisms by which p53 determines cell-fate decisions.
XAF1, p53, HIPK2, Siah2, ZNF313
1To whom correspondence should be addressed.
Author contributions: M.-G.L. and S.-G.C. designed research; M.-G.L., J.H., S.-I.J., N.-G.H., J.-H.L., T.-K.H., M.-J.K., and B.-K.R. performed research; J.H., S.-I.J., N.-G.H., J.-H.L., T.-K.H., M.-J.K., B.-K.R., and S.-G.C. analyzed data; and M.-G.L. and S.-G.C. wrote the paper
논문정보
- Research article
- 2014년 10월 (BRIC 등록일 2014-10-17)
- 국내 연구진
- 생명과학 > 노화/암생물학
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