Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor

被引：461

作者：

Fan, ZS

Beresford, PJ

Oh, DY

Zhang, D

Lieberman, J ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

来源：

CELL | 2003年 / 112卷 / 05期

关键词：

D O I：

10.1016/S0092-8674(03)00150-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Granzyme A (GzmA) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GzmA-activated DNase (GAAD) is in an ER associated complex containing pp32 and the GzmA substrates SET, HMG-2, and Ape1. We show that GAAD is NM23-H1, a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor (IGAAD) is SET. NM23-H1 binds to SET and is released from inhibition by GzmA cleavage of SET. After GzmA loading or CTL attack, SET and NM23-H1 translocate to the nucleus and SET is degraded, allowing NM23-H1 to nick chromosomal DNA. GzmA-treated cells with silenced NM23-H1 expression are resistant to GzmA-mediated DNA damage and cytolysis, while cells over-expressing NM23-H1 are more sensitive.

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页码：659 / 672

页数：14

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