ABSTRACT
Orderly progression through the normal cell cycle involves a coordinated series of activation and inactivation steps monitored by cyclin and CDK enzyme complexes. The regulatory subunit (cyclin) heterodimerizes with its catalytic partner (CDK) to form holoenzymes that are activated by phosphorylation (Morgan, 1995) and, in turn, phosphorylate key target substrates. Phosphorylation and activation of these substrates lead to cell cycle progression (reviewed in Liu, Marshall et al., 2004). At least 13 CDKs and 25 proteins with homology in the cyclin box domain have been identified in the human genome. Transition through the mid and late G
phase of the cell cycle is promoted by the D-type cyclins and by cyclin E in late G
phase. Cyclin D1 was initially cloned by three different groups of investigators (Matsushime, Roussel et al., 1991; Motokura, Bloom et al., 1991; Xiong, Connolly et al., 1991; Geisen and Moroy, 2002). The human cyclin D1 gene was cloned during the analysis
PTH
gene in parathyroid adenomas and was as a G
cyclin on the basis of its ability to complement mutations of the CLN genes in budding yeast (Koff, Cross et al., 1991; Lew, Dulic et al., 1991). Cyclin E1 as well as a second E-type cyclin (cyclin E2, Lauper, Beck et al., 1998) function as activators of CDK2 (reviewed in Moroy and Geisen, 2004). Cyclin D1 abundance is labile and both growth factor-and oncogene-inducible; cyclin D1 kinase activity rises 6 h after serum stimulation, with cyclin D1 in complex with CDK4 or CDK6, to phosphorylate and inactivate the retinoblastoma (Rb) protein. Cyclin E levels rise sequentially, allowing the formation of cyclin E/CDK2 complexes, with levels subsequently declining upon degradation through the SCF (Fbw7) ubiquitin ligase (Carrano, Eytan et al., 1999; Sutterluty, Chatelain et al., 1999; Tomoda, Kubota et al., 1999; Tsvetkov, Yeh et al., 1999; Nakayama, Nagahama et al., 2000; Rodier, Montagnoli et al., 2001; Ishida, Hara et al., 2002) and KPC (Kamura, Hara et al., 2004). Cyclin E functions to promote the assembly of a pre-replication complex through loading CDC6 to the origins of replication and recruiting MCM2 to several proteins. CDK2/cyclin E kinase phosphorylates Rb and Rb-related proteins, together with several other substrates, including those involved in pre-mRNA splicing, histone biosynthesis, centrosome duplication, CDC25, and p27
, a cyclin-dependent kinase inhibitor (Moroy and Geisen, 2004).
