The tumor-specific hyperactive forms of cyclin E are resistant to inhibition by p21 and p27

被引:54
作者
Wingate, H
Zhang, N
McGarhen, MJ
Bedrosian, I
Harper, JW
Keyomarsi, K
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA
[3] Univ Texas, Hlth Sci Ctr, Grad Sch Biomed Sci, Canc Biol Program, Houston, TX 77030 USA
[4] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.M409789200
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 low molecular weight (LMW) isoforms of cyclin E are unique to cancer cells. In breast cancer, such alteration of cyclin E is a very strong predictor of poor patient outcome. Here we show that alteration in binding properties of these LMW isoforms to CDK2 and the CDK inhibitors (CKIs), p21 and p27, results in their functional hyperactivity. The LMW forms of cyclin E are severalfold more effective at binding to CDK2. Additionally, compared with the full-length cyclin E-CDK2 complexes, the LMW cyclin E-CDK2 complexes are significantly more resistant to inhibition by p21 and p27, despite equal binding of the CKIs to the LMW complexes. When both the full-length and the LMW cyclin E are co-expressed, p27 preferentially binds to the LMW forms yet is unable to inhibit the CDK2 activity. Thus, the LMW forms of cyclin E may contribute to tumorigenesis through their resistance to the inhibitory activities of p21 and p27 while sequestering these CKIs from the full-length cyclin E.
引用
收藏
页码:15148 / 15157
页数:10
相关论文
共 56 条
[1]   Removal of Cdk inhibitors through both sequestration and downregulation in zearalenone-treated MCF-7 breast cancer cells [J].
Ahamed, S ;
Foster, JS ;
Bukovsky, A ;
Diehl, JA ;
Wimalasena, J .
MOLECULAR CARCINOGENESIS, 2002, 34 (01) :45-58
[2]   Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p2l, p27, and antiestrogens in breast cancer [J].
Akli, S ;
Zheng, PJ ;
Multani, AS ;
Wingate, HF ;
Pathak, S ;
Zhang, N ;
Tucker, SL ;
Chang, S ;
Keyomarsi, K .
CANCER RESEARCH, 2004, 64 (09) :3198-3208
[3]   Regulation of G1 cyclin-dependent kinases in the liver:: role of nuclear localization and p27 sequestration [J].
Albrecht, JH ;
Rieland, BM ;
Nelsen, CJ ;
Ahonen, CL .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 1999, 277 (06) :G1207-G1216
[4]   CYCLIN D1 IS A NUCLEAR-PROTEIN REQUIRED FOR CELL-CYCLE PROGRESSION IN G(1) [J].
BALDIN, V ;
LUKAS, J ;
MARCOTE, MJ ;
PAGANO, M ;
DRAETTA, G .
GENES & DEVELOPMENT, 1993, 7 (05) :812-821
[5]  
BARRETT AJ, 1986, RES MONOG CELL TISSU, V12, P515
[6]   Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27 [J].
Bouchard, C ;
Thieke, K ;
Maier, A ;
Saffrich, R ;
Hanley-Hyde, J ;
Ansorge, W ;
Reed, S ;
Sicinski, P ;
Bartek, J ;
Eilers, M .
EMBO JOURNAL, 1999, 18 (19) :5321-5333
[7]  
BUCKLEY MF, 1993, ONCOGENE, V8, P2127
[8]  
Ciaparrone M, 1998, CANCER RES, V58, P114
[9]   ASSOCIATION OF HUMAN CYCLIN-E WITH A PERIODIC G(1)-S PHASE PROTEIN-KINASE [J].
DULIC, V ;
LEES, E ;
REED, SI .
SCIENCE, 1992, 257 (5078) :1958-1961
[10]   FUNCTIONAL INTERACTIONS OF THE RETINOBLASTOMA PROTEIN WITH MAMMALIAN D-TYPE CYCLINS [J].
EWEN, ME ;
SLUSS, HK ;
SHERR, CJ ;
MATSUSHIME, H ;
KATO, JY ;
LIVINGSTON, DM .
CELL, 1993, 73 (03) :487-497