E3 ubiquitin ligase Hades negatively regulates the exonuclear function of p53

被引：44

作者：

Jung, J. H. ^{[1
]}

Bae, S. ^{[1
]}

Lee, J. Y. ^{[1
]}

Woo, S. R. ^{[2
]}

Cha, H. J. ^{[1
]}

Yoon, Y. ^{[1
]}

Suh, K-S ^{[3
]}

Lee, S-J ^{[4
]}

Park, I-C ^{[5
]}

Jin, Y-W ^{[6
]}

Lee, K-H ^{[2
]}

An, S. ^{[1
,7
]}

Lee, J. H. ^{[1
]}

机构：

[1] Konkuk Univ, Funct Genoproteome Res Ctr, Seoul 143701, South Korea

[2] Korea Inst Radiol & Med Sci, Lab Radiat Mol Canc, Seoul, South Korea

[3] Seoul Natl Univ, Sch Med, Dept Surg, Seoul, South Korea

[4] Hanyang Univ, Dept Chem, Seoul 133791, South Korea

[5] Korea Inst Radiol & Med Sci, Lab Funct Genom, Seoul, South Korea

[6] Radiat Hlth Res Inst KHNP, Div Radiat Effect Res, Seoul, South Korea

[7] Konkuk Univ, LIFEnGENE Inc, Seoul 143701, South Korea

来源：

CELL DEATH AND DIFFERENTIATION | 2011年 / 18卷 / 12期

关键词：

p53; ubiquitination; E3; ligase; CELL-CYCLE; TRANSCRIPTIONAL ACTIVATION; WILD-TYPE; APOPTOSIS; PROTEIN; MITOCHONDRIA; LOCALIZATION; SUPPRESSOR; MUTANTS; DOMAIN;

D O I：

10.1038/cdd.2011.57

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：

Following DNA damage, p53 translocates to the cytoplasm and mitochondria, where it triggers transcription-independent apoptosis by binding to Bcl-2 family proteins. However, little is known about how this exonuclear function of p53 is regulated. Here, we identify and characterize a p53-interacting protein called Hades, an E3 ligase that interacts with p53 in the mitochondria. Hades reduces p53 stability via a mechanism that requires its RING-finger domain with ubiquitin ligase activity. Hades polyubiquitinates p53 in vitro independent of Mdm2 and targets a critical lysine residue in p53 (lysine 24) distinct from those targeted by Mdm2. Hades inhibits a p53-dependent mitochondrial cell death pathway by inhibiting p53 and Bcl-2 interactions. These findings show that Hades-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53. Cell Death and Differentiation (2011) 18, 1865-1875; doi:10.1038/cdd.2011.57; published online 20 May 2011

引用

页码：1865 / 1875

页数：11

共 35 条

[1] MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission [J].

Braschi, Emelie ;

Zunino, Rodolfo ;

McBride, Heidi M. .

EMBO REPORTS, 2009, 10 (07) :748-754

[2] p53 ubiquitination: Mdm2 and beyond [J].

Brooks, CL ;

Gu, W .

MOLECULAR CELL, 2006, 21 (03) :307-315

[3] P53-DEPENDENT APOPTOSIS IN THE ABSENCE OF TRANSCRIPTIONAL ACTIVATION OF P53-TARGET GENES [J].

CAELLES, C ;

HELMBERG, A ;

KARIN, M .

NATURE, 1994, 370 (6486) :220-223

[4] ARF-BP1/mule is a critical mediator of the ARF tumor suppressor [J].

Chen, DL ;

Kon, N ;

Li, MY ;

Zhang, WZ ;

Qin, J ;

Gu, W .

CELL, 2005, 121 (07) :1071-1083

[5] Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis [J].

Chipuk, JE ;

Kuwana, T ;

Bouchier-Hayes, L ;

Droin, NM ;

Newmeyer, D ;

Schuler, M ;

Green, DR .

SCIENCE, 2004, 303 (5660) :1010-1014

[6] The ubiquitin ligase COP1 is a critical negative regulator of p53 [J].

Dornan, D ;

Wertz, I ;

Shimizu, H ;

Arnott, D ;

Frantz, GD ;

Dowd, P ;

O' Rourke, K ;

Koeppen, H ;

Dixit, VM .

NATURE, 2004, 429 (6987) :86-92

[7] P53-DEPENDENT INHIBITION OF CYCLIN-DEPENDENT KINASE-ACTIVITIES IN HUMAN FIBROBLASTS DURING RADIATION-INDUCED G1 ARREST [J].

DULIC, V ;

KAUFMANN, WK ;

WILSON, SJ ;

TLSTY, TD ;

LEES, E ;

HARPER, JW ;

ELLEDGE, SJ ;

REED, SI .

CELL, 1994, 76 (06) :1013-1023

[8] THE P53 PROTO-ONCOGENE CAN ACT AS A SUPPRESSOR OF TRANSFORMATION [J].

FINLAY, CA ;

HINDS, PW ;

LEVINE, AJ .

CELL, 1989, 57 (07) :1083-1093

[9] The MDM2 RING-finger domain is required to promote p53 nuclear export [J].

Geyer, RK ;

Yu, ZK ;

Maki, CG .

NATURE CELL BIOLOGY, 2000, 2 (09) :569-573

[10] Cytoplasmic functions of the tumour suppressor p53 [J].

Green, Douglas R. ;

Kroemer, Guido .

NATURE, 2009, 458 (7242) :1127-1130

← 1 2 3 4 →