Regulation of G1/S transition in mammalian cells

The entry of a cell into DNA synthesis is a critical entry, but the way in which this enzyme promotes DNA synthesis is poorly understood because few substrates regulation point for all living cells. A number of cyclins have been identified. We are currently using a variety and cyclin-dependent kinases (CDKs) have been impliof techniques to identify new substrates for cyclin cated in the G1/S phase cell cycle transition. E/cdk2. Two novel complexes have been identified: the The D-type cyclins and their kinase partners CDK4 U2 complex of the splicing machinery and also compoand CDK6 are involved in regulating the entry of cells nents of the SWI/SNF chromatin remodeling apparatus. into the cell cycle from a quiescent state. It is believed that unique mechanisms may serve to regulate these REFERENCES early induced cyclin-dependent kinases. We have observed that in addition to post-translational modifica1. Lees EM: Cyclin dependent kinase regulation. Curr Opin Cell Biol 7:773–780, 1995 tions, as previously described, novel protein–protein in2. Sherr CJ: Cancer cell cycles. Science 274:1672–1677, 1996 teractions may also serve to regulate the activity of 3. Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon CDK4 and CDK6 complexes. The respective roles of M: Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell the INK4 and p21 family of cyclin-dependent kinase Biol 17:5598–5611, 1997 inhibitors in regulating their activity have been analyzed. 4. Seghezzi W, Chua K, Shanahan F, Gozani O, Reed R, Lees E: Cyclin E associates with components of the pre-mRNA splicing Our data support the model that INK4 proteins form machinery in mammalian cells. Mol Cell Biol 18:4526–4536, 1998 very stable complexes with CDKs and that a disruption 5. Mahony D, Parry DA, Lees E: Active cdk6 complexes are predomiof these complexes by the p21/p27 proteins is required nantly nuclear and represent only a minority of the cdk6 in T cells. Oncogene 16:603–611, 1998 to get cyclin/CDK assembly. p21/p27 therefore plays an 6. Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E: Cyclin E important positive role in facilitating CDK4 assembly in associates with BAF155 and BRG1, components of the mammalian response to mitogenic stimuli. It remains to be estabSWI/SNF complex, and alters the ability of BRG1 to induce growth arrest. Mol Cell Biol 19:1460–1469, 1999 lished why p21 should be an activator for CDK4 and yet 7. Parry D, Mahony D, Wills K, Lees E: D cyclin/CDK arrangement also a very potent inhibitor of CDK2. is dependent on availability of competing p21 and p16 class inhibiThe cyclin E/CDK2 complex is essential for S-phase tors. Mol Cell Biol 19:1775–1783, 1999