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Proc. Natl. Acad. Sci. USA, Published online before print May 15, 2017 | doi: 10.1073/pnas.1700861114 Identification of XAF1–MT2A mutual antagonism as a molecular switch in cell-fate decisions under stressful conditions

Cheol-Hee Shin^a, Min-Goo Lee^a, Jikhyon Han^a, Seong-In Jeong^a, Byung-Kyu Ryu^a, and Sung-Gil Chi^a,1^aDepartment of Life Sciences, Korea University, Seoul 02841, Korea
¹To whom correspondence should be addressed.

Author contributions: C.-H.S., M.-G.L., and S.-G.C. designed research; C.-H.S., M.-G.L., J.H., S.-I.J., and B.-K.R. performed research; C.-H.S., M.-G.L., J.H., S.-I.J., B.-K.R., and S.-G.C. analyzed data; and C.-H.S. and S.-G.C. wrote the paper.

Abstract

XIAP-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human neoplasms. However, the molecular mechanism underlying its proapoptotic function remains largely undefined. Here, we report that XAF1 induction by heavy metals triggers an apoptotic switch of stress response by destabilizing metallothionein 2A (MT2A). XAF1 directly interacts with MT2A and facilitates its lysosomal degradation, resulting in the elevation of the free intercellular zinc level and subsequent activation of p53 and inactivation of XIAP. Intriguingly, XAF1 is activated as a unique transcription target of metal-regulatory transcription factor-1 (MTF-1) in signaling apoptosis, and its protein is destabilized via the lysosomal pathway by MTF-1-induced MT2A under cytostatic stress conditions, indicating the presence of mutual antagonism between XAF1 and MT2A. The antagonistic interplay between XAF1 and MT2A acts as a key molecular switch in MTF-1-mediated cell-fate decisions and also plays an important role in cell response to various apoptotic and survival factors. Wild-type (WT) XAF1 but not MT2A binding-deficient mutant XAF1 increases the free intracellular zinc level and accelerates WT folding of p53 and degradation of XIAP. Consistently, XAF1 evokes a more drastic apoptotic effect in p53^+/+ versus isogenic p53^-/- cells. Clinically, expression levels of XAF1 and MT2A are inversely correlated in primary colon tumors and multiple cancer cell lines. XAF1-depleted xenograft tumors display an increased growth rate and a decreased apoptotic response to cytotoxic heavy metals with strong MT2A expression. Collectively, this study uncovers an important role for XAF1-MT2A antagonism as a linchpin to govern cell fate under various stressful conditions including heavy metal exposure.

XAF1, metallothionein, MTF-1, heavy metal, apoptosis

논문정보

형식Research article
게재일2017년 05월 (BRIC 등록일 2017-05-22)
연구진국내 연구진
분야 생명과학 > 노화/암생물학

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