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Department of Cell Biology Faculty
Stacy Blain, Ph.D.
Department of Pediatrics, Box 49
Tel: (718) 270-4471 • Fax: (718) 270-1699
Regulation of G1 Cdks and Ckis During the Cell Cycle and Cancer
The principal task of the cell cycle is to ensure that a cell's DNA is faithfully duplicated and evenly distributed to daughter cells. Loss of control over this process is a hallmark of cancer. Indeed, direct perturbation of most genes involved in cell cycle control has been observed in human cancers. Cell cycle transitions are tightly controlled by the actions of the cyclin-cdks. These kinases act by phosphorylating and inactivating substrates, such as the tumor suppressor Rb, which prevent S phase entry. Cdk activity is regulated by a combination of mechanisms, including changes in the cyclin or cdk levels, phosphorylation of positive and negative regulatory sites, and interaction with stoichiometric inhibitors (ckis), such as p27. During periods of cell proliferation, p27 remains in storage by binding to two G1 cdks, cdk4 or cdk6, in a non-inhibitory fashion. Anti-mitogenic signals, including the cytokine transforming growth factor-b and cell-cell contact, mobilize stored p27 enabling it to bind and inhibit another cdk, cdk2.The regulation of cyclin-cdks by inhibitors appears to be an important step in linking mitogenic or antimitogenic signals to cell cycle progression.
Our lab is studying the mechanisms by which the G1 cdks and ckis are regulated and activated in the cell. Specifically, we hope to address several fundamental questions: 1) How is the function of cdk4 and cdk6 different during asynchronous growth and following release from quiescence? 2) What are the signals that activate and inactive cdk4 and cdk6? 3) Are cdk4 and cdk6 truly redundant? 4) Are there conditions where p27 is inhibitory to cdk4 or cdk6 in vivo? Alterations in the p16-cyclin D-cdk4/6-Rb pathway are found in almost all human cancers, suggesting that this pathway must be deregulated in order for a cell to progress to malignancy. A decrease in p27 levels, owing to an increased degradation of the protein, is detected in roughly half of carcinomas and correlates with aggressive, high grade tumors of poor prognosis. A more complete understanding of these pathway is therefore required to understand the signals that promote cancer progression.
SELECTED RECENT PUBLICATIONS
1)Ye W, S. W. Blain. Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage.(2011) Apoptosis. 16(5):449-59
2) Nguyen KD, Blain SW, Gress F, Treem WR. Inflammatory mediators of esophagitis alter p27 Kip1 expression in esophageal epithelial cells. (2010) J Pediatr Gastroenterol Nutr. 51(5):556-62.
3) Ye W, S. W. Blain. S phase entry causes homocysteine-induced death while ataxia telangiectasia and Rad3 related protein functions anti-apoptotically to protect neurons.(2010) Brain 133(Pt 8):2295-312.
4) Ray, A., James, M, Larochelle, S., Fisher, R. and S. W. Blain. p27Kip1 inhibits cyclin D-cdk4 by two independent modes. (2009) Mol. Cell. Biol. 29: 986-9.
5) Blain, S. W. Switching cyclin D-cdk4 on and off. (2008) Cell Cycle. 7:892-898.
6) James, M., Ray, A , Leznova, D. and Blain, S. W. Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity. (2008) Mol. Cell. Biol. 28:498-510
7) Blain, S. W. Scher, H. I.,Cordon-Cardo, C., and Koff, A. p27 as a target for cancer therapeutics. (2003) Cancer Cell 3: 111-115.
8) Blain, S. W. and Massagué, J. Breast cancer protein banned from nucleus. (2002) Nature Med. 8:1076--8
9) Massagué, J., Blain, S. W. Lo. R. S. TGF-beta signaling in growth control, cancer, and heritable disorders. (2000) Cell 103: 295-309.
10) Blain, S. W. and Massagué, J. Different sensitivity of the TGF-beta cell cycle arrest pathway to c-Myc and MDM-2. (2000) J. Biol. Chem. 272: 25863-25872.
11) Warner, B. J., Blain, S. W., Seoane, J. and Massagué, J. Myc downregulation by Transforming growth factor-beta is required for activation of the p15Ink4b G1 arrest pathway. Mol. Cell. Biol. 19: 5913-5922.
12) Blain, S. W., Montalvo, E. and Massagué, J. Differential interaction of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 with cyclin A-cdk2 and cyclin D2-cdk4. (1997) J. Biol. Chem. 272: 25863-25872.