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J. Biol. Chem., Vol. 281, Issue 22, 15304-15311, June 2, 2006

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Distinct Domains for Anti- and Pro-apoptotic Activities of IEX-1^*

From the Wellman Center of Photomedicine, Massachusetts General Hospital, and the Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02114

IEX-1 (immediate early response gene X-1) is a stress-inducible gene. Its overexpression can suppress or enhance apoptosis dependent on the nature of stress, yet the polypeptide does not possess any of the functional domains that are homologous to those present in well characterized effectors or inhibitors of apoptosis. This study using sequence-targeting mutagenesis reveals a transmembrane-like integrated region of the protein to be critical for both pro-apoptotic and anti-apoptotic functions. Substitution of the key hydrophobic residues with hydrophilic ones within this region impairs the capacity IEX-1 to positively and negatively regulate apoptosis. Mutations at N-linked glycosylation and phosphorylation sites or truncation of the C terminus of IEX-1 also abrogated its potential to promote cell survival. However, distinguished from the transmembrane-like domain, these mutants preserved pro-apoptotic activity of IEX-1 fully. On the contrary, mutation of nuclear localization sequence, despite its importance in apoptosis, did not impede IEX-1-mediated cell survival. Strikingly, all the mutants that lose their anti-apoptotic ability are unable to prevent acute increases in production of intracellular reactive oxygen species (ROS) at the initial onset of apoptosis, whereas those mutants that can sustain anti-death function also control acute ROS production as sufficiently as wild-type IEX-1. These findings suggest a critical role of IEX-1 in regulation of intracellular ROS homeostasis, providing new insight into the mechanism underlying IEX-1-mediated cell survival.

Received for publication, January 3, 2006 , and in revised form, March 15, 2006.

^* This work was supported by National Institutes of Health Grant AI050822, Research Scholar Grant RSG-01-178-01-MGO from the American Cancer Society, and a Moran foundation award (Grant PRJ 00–114) from the Baylor College of Medicine (to M. X. 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.

¹ To whom correspondence should be addressed: Wellman Center for Photomedicine, Massachusetts General Hospital, Edwards 222, 50 Blossom St., Boston, MA 02114. Tel.: 617-726-1298; Fax: 617-726-1206; E-mail: mwu2{at}partners.org.

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