LATS1 tumor suppressor regulates G2/M transition and apoptosis

被引:134
作者
Xia, H
Qi, HL
Li, YF
Pei, J
Barton, J
Blackstad, M
Xu, T
Tao, WF [1 ]
机构
[1] Univ Minnesota, Ctr Canc, Div Hematol Oncol & Transplantat, Stem Cell Inst, Minneapolis, MN 55455 USA
[2] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06536 USA
关键词
LATS1; tumor suppressor; G2/M transition; apoptosis;
D O I
10.1038/sj.onc.1205174
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
The LATS1 gene is a mammalian member of the novel lats tumor suppressor family. Both lats mosaic flies and LATS1 deficient mice spontaneously develop tumors. Our previous studies have shown that inactivation of Drosophila lats leads to up-regulation of cyclin A in the fly, and the human LATS1 protein associates with CDC2 in early mitosis in HeLa cells, suggesting that the lats gene family may negatively regulate cell proliferation by modulating CDC2/Cyclin A activity. We demonstrate here that transduction of the human breast cancer cell MCF-7 with recombinant LATS1 adenovirus (Ad-LATS1), but not with EGFP adenovirus (Ad-EGFP), inhibits in vitro cell proliferation. Ectopic expression of LATS1 in MCF-7 cells specifically downregulates Cyclin A and Cyclin B protein levels and dramatically reduces CDC2 kinase activity, leading to a G2/M blockade. Furthermore, Ad-LATS] suppresses anchorage-independent growth of MCF-7 cells in soft agar and tumor formation in athymic nude mice. We also demonstrate that ectopic expression of LATS1 in MCF-7 cells and human lung cancer cell H460 upregulates the level of BAX proteins and induces apoptosis. Finally, we show that LATS1 kinase activity is required for its ability to inhibit cell growth and induce apoptosis. The results indicate that the LATS1 tumor suppressor may play an important role in the control of human tumor development and that LATS1 suppresses tumorigenesis by negatively regulating cell proliferation and modulating cell survival.
引用
收藏
页码:1233 / 1241
页数:9
相关论文
共 40 条
[11]   Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor [J].
Hirota, T ;
Morisaki, T ;
Nishiyama, Y ;
Marumoto, T ;
Tada, K ;
Hara, T ;
Masuko, N ;
Inagaki, M ;
Hatakeyama, K ;
Saya, H .
JOURNAL OF CELL BIOLOGY, 2000, 149 (05) :1073-1086
[12]   Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a Drosophila tumor suppressor [J].
Hori, T ;
Takaori-Kondo, A ;
Kamikubo, Y ;
Uchiyama, T .
ONCOGENE, 2000, 19 (27) :3101-3109
[13]   CYCLINS AND CANCER .2. CYCLIN-D AND CDK INHIBITORS COME OF AGE [J].
HUNTER, T ;
PINES, J .
CELL, 1994, 79 (04) :573-582
[14]   THE DROSOPHILA TUMOR-SUPPRESSOR GENE WARTS ENCODES A HOMOLOG OF HUMAN MYOTONIC-DYSTROPHY KINASE AND IS REQUIRED FOR THE CONTROL OF CELL-SHAPE AND PROLIFERATION [J].
JUSTICE, RW ;
ZILIAN, O ;
WOODS, DF ;
NOLL, M ;
BRYANT, PJ .
GENES & DEVELOPMENT, 1995, 9 (05) :534-546
[15]   How proteolysis drives the cell cycle [J].
King, RW ;
Deshaies, RJ ;
Peters, JM ;
Kirschner, MW .
SCIENCE, 1996, 274 (5293) :1652-1659
[16]   MITOSIS IN TRANSITION [J].
KING, RW ;
JACKSON, PK ;
KIRSCHNER, MW .
CELL, 1994, 79 (04) :563-571
[17]   Recombinant PML adenovirus suppresses growth and tumorigenicity of human breast cancer cells by inducing G1 cell cycle arrest and apoptosis [J].
Le, XF ;
Vallian, S ;
Mu, ZM ;
Hung, MC ;
Chang, KS .
ONCOGENE, 1998, 16 (14) :1839-1849
[18]  
LEE JH, 1990, CANCER RES, V50, P2724
[19]  
Mazurenko N, 1999, ONCOL REP, V6, P859
[20]  
MIYASHITA T, 1995, CELL, V80, P293