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During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).
During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.