PINCH-1 regulates the ERK-Bim pathway and contributes to apoptosis resistance in cancer cells

被引:67
作者
Chen, Ka [1 ]
Tu, Yizeng [1 ]
Zhang, Yongjun [1 ]
Blair, Harry C. [1 ]
Zhang, Lin [2 ,3 ]
Wu, Chuanyue [1 ,3 ]
机构
[1] Univ Pittsburgh, Dept Pathol, Sch Med, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Dept Pharmacol, Sch Med, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Inst Canc, Sch Med, Pittsburgh, PA 15261 USA
关键词
D O I
10.1074/jbc.M707307200
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
Resistance to apoptosis is a hallmark of cancer cells. We report here that PINCH-1, a cytoplasmic component of cell-extracellular matrix adhesions, is required for protection of multiple types of cancer cells from apoptosis. Furthermore, using HT-1080 fibrosarcoma cells as a model system, we have investigated the signaling pathway through which PINCH-1 contributes to apoptosis resistance. Loss of PINCH-1 markedly increases the level of Bim and promotes Bim translocation to mitochondria, resulting in activation of the intrinsic apoptosis pathway. Depletion of Bim completely blocked apoptosis induced by the loss of PINCH-1.Thus, PINCH-1 contributes to apoptosis resistance through suppression of Bim. Mechanistically, PINCH-1 suppresses Bim not only transcriptionally but also post-transcriptionally. PINCH-1 promotes activating phosphorylation of Src family kinase and ERK1/2. Consistent with this, ERK1/2-mediated Ser69 phosphorylation of Bim, a key signal for turnover of Bim, is suppressed by the removal of PINCH-1. Our results demonstrate a strong dependence of multiple types of apoptosis-resistant cancer cells on PINCH-1 and provide new insights into the molecular mechanism by which cancer cells are protected from apoptosis.
引用
收藏
页码:2508 / 2517
页数:10
相关论文
共 60 条
[1]   Ways of dying: multiple pathways to apoptosis [J].
Adams, JM .
GENES & DEVELOPMENT, 2003, 17 (20) :2481-2495
[2]   Cell adhesion molecules, signal transduction and cell growth [J].
Aplin, AE ;
Howe, AK ;
Juliano, RL .
CURRENT OPINION IN CELL BIOLOGY, 1999, 11 (06) :737-744
[3]   Adhesion-dependent cell mechanosensitivity [J].
Bershadsky, AD ;
Balaban, NQ ;
Geiger, B .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2003, 19 :677-695
[4]   Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].
Brunet, A ;
Bonni, A ;
Zigmond, MJ ;
Lin, MZ ;
Juo, P ;
Hu, LS ;
Anderson, MJ ;
Arden, KC ;
Blenis, J ;
Greenberg, ME .
CELL, 1999, 96 (06) :857-868
[5]   Requirement for p53 and p21 to sustain G2 arrest after DNA damage [J].
Bunz, F ;
Dutriaux, A ;
Lengauer, C ;
Waldman, T ;
Zhou, S ;
Brown, JP ;
Sedivy, JM ;
Kinzler, KW ;
Vogelstein, B .
SCIENCE, 1998, 282 (5393) :1497-1501
[6]   Analysis of PINCH function in Drosophila demonstrates its requirement in integrin-dependent cellular processes [J].
Clark, KA ;
McGrail, M ;
Beckerle, MC .
DEVELOPMENT, 2003, 130 (12) :2611-2621
[7]   Cell death: Critical control points [J].
Danial, NN ;
Korsmeyer, SJ .
CELL, 2004, 116 (02) :205-219
[8]   Integrin cytoplasmic interactions and bidirectional transmembrane signalling [J].
Dedhar, S ;
Hannigan, GE .
CURRENT OPINION IN CELL BIOLOGY, 1996, 8 (05) :657-669
[9]   A decade of caspases [J].
Degterev, A ;
Boyce, M ;
Yuan, JY .
ONCOGENE, 2003, 22 (53) :8543-8567
[10]   Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 [J].
Dijkers, PF ;
Medema, RH ;
Lammers, JWJ ;
Koenderman, L ;
Coffer, PJ .
CURRENT BIOLOGY, 2000, 10 (19) :1201-1204