Runt-Related Transcription Factor RUNX3 Is a Target of MDM2-Mediated Ubiquitination

被引:45
作者
Chi, Xin-Zi [1 ]
Kim, Jiyeon [1 ]
Lee, Yong-Hee [1 ]
Lee, Jung-Won [1 ]
Lee, Kyeong-Sook [1 ]
Wee, Heejun [1 ]
Kim, Wun-Jae [2 ]
Park, Woo-Yoon [3 ]
Oh, Byung-Chul [4 ]
Stein, Gary S. [5 ,6 ]
Ito, Yoshiaki [7 ]
van Wijnen, Andre J. [5 ,6 ]
Bae, Suk-Chul [1 ]
机构
[1] Chungbuk Natl Univ, Inst Tumor Res, Coll Med, Dept Biochem, Cheongju 361763, Chungbuk, South Korea
[2] Chungbuk Natl Univ, Inst Tumor Res, Coll Med, Dept Urol, Cheongju 361763, Chungbuk, South Korea
[3] Chungbuk Natl Univ, Coll Med, Dept Radiat Oncol, Cheongju 361763, Chungbuk, South Korea
[4] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea
[5] Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA
[6] Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01655 USA
[7] Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore
关键词
CLEIDOCRANIAL DYSPLASIA; OSTEOBLAST DIFFERENTIATION; POINT MUTATIONS; CELL-GROWTH; P53; MDM2; DOMAIN; GENE; BINDING; CANCER;
D O I
10.1158/0008-5472.CAN-09-1057
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The p14(ARF)-MDM2-p53 pathway constitutes an effective mechanism for protecting cells from oncogenic stimuli such as activated Ras and Myc. Importantly, Ras activation induces p14(ARF) and often occurs earlier than p53 inactivation during cancer development. Here, we show that RUNX3, a tumor suppressor in various tumors including stomach, bladder, colon, and lung, is stabilized by Ras activation through the p14(ARF)-MDM2 signaling pathway. RUNX3 directly binds MDM2 through its Runt-related DNA-binding domain. MDM2 blocks RUNX3 transcriptional activity by interacting with RUNX3 through an acidic domain adjacent to the p53-binding domain of MDM2 and ubiquitinates RUNX3 on key lysine residues to mediate nuclear export and proteasomal degradation. Our data indicate that the lineage-specific tumor suppressor RUNX3 and the ubiquitous p53 protein are both principal responders of the p14(ARF)-MDM2 cell surveillance pathway that prevents pathologic consequences of abnormal oncogene activation. [Cancer Res 2009;69(20):8111-9]
引用
收藏
页码:8111 / 8119
页数:9
相关论文
共 48 条
[1]   Tumor suppressor activity of RUNX3 [J].
Bae, SC ;
Choi, JK .
ONCOGENE, 2004, 23 (24) :4336-4340
[2]   Mammalian G1- and S-phase checkpoints in response to DNA damage [J].
Bartek, J ;
Lukas, J .
CURRENT OPINION IN CELL BIOLOGY, 2001, 13 (06) :738-747
[3]   The RUNX genes: Gain or loss of function in cancer [J].
Blyth, K ;
Cameron, ER ;
Neil, JC .
NATURE REVIEWS CANCER, 2005, 5 (05) :376-387
[4]   p53 ubiquitination: Mdm2 and beyond [J].
Brooks, CL ;
Gu, W .
MOLECULAR CELL, 2006, 21 (03) :307-315
[5]  
Cazorla M, 1998, MOL CARCINOGEN, V21, P251, DOI 10.1002/(SICI)1098-2744(199804)21:4<251::AID-MC4>3.0.CO
[6]  
2-N
[7]   MAPPING OF THE P53 AND MDM-2 INTERACTION DOMAINS [J].
CHEN, JD ;
MARECHAL, V ;
LEVINE, AJ .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (07) :4107-4114
[8]   RUNX3 suppresses gastric epithelial cell growth by inducing p21WAF1/Cip1 expression in cooperation with transforming growth factor β-activated SMAD [J].
Chi, XZ ;
Yang, JO ;
Lee, KY ;
Ito, K ;
Sakakura, C ;
Li, QL ;
Kim, HR ;
Cha, EJ ;
Lee, YH ;
Kaneda, A ;
Ushijima, T ;
Kim, WJ ;
Ito, Y ;
Bae, SC .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (18) :8097-8107
[9]  
CORDONCARDO C, 1994, CANCER RES, V54, P794
[10]   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