Mitotic G1 phase and G1/S transition

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Homo sapiens
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Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

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.

Literature References
PubMed ID Title Journal Year
17244524 Life without kinase: cyclin E promotes DNA replication licensing and beyond

Zhang, H

Mol. Cell 2007
9724731 The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase

Robin, P, Harel-Bellan, A, Magnaghi-Jaulin, L, Trouche, D, Ferreira, R

Proc Natl Acad Sci U S A 1998
1828394 The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein

Chittenden, T, Kaelin, WG, Livingston, DM

Cell 1991
15838516 Pocket proteins and cell cycle control

Cobrinik, D

Oncogene 2005
9508775 A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes

Depoortere, F, Dumont, JE, Van Keymeulen, A, Costagliola, S, Dremier, S, Roger, PP, Lukas, J, Bartkova, J, Bartek, J

J. Cell Biol. 1998
9448290 Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1)

Sexl, V, Sherr, CJ, Cheng, M, Roussel, MF

Proc. Natl. Acad. Sci. U.S.A. 1998
8001816 Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function

Matera, AG, Xiong, Y, Guan, KL, Nichols, MA, Li, Y, O'Keefe, CL, Wu, X, Jenkins, CW

Genes Dev 1994
8078588 p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest

Hannon, GJ, Beach, D

Nature 1994
1828392 The E2F transcription factor is a cellular target for the RB protein

Nevins, JR, Hiebert, S, Chellappan, SP, Horowitz, JM, Mudryj, M

Cell 1991
8246996 The retinoblastoma protein binds to a family of E2F transcription factors

Saito, M, Dyson, N, Vidal, M, Helin, K, Harlow, E, Valentine, M, Look, T, Lees, JA

Mol. Cell. Biol. 1993
23842645 The DREAM complex: master coordinator of cell cycle-dependent gene expression

Sadasivam, S, DeCaprio, JA

Nat. Rev. Cancer 2013
10773440 Cell-cycle inhibitors: three families united by a common cause

Vidal, A, Koff, A

Gene 2000
8741839 Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4

Matera, AG, Xiong, Y, Guan, KL, Zariwala, M, Li, Y, O'Keefe, CL, Noh, S, Wu, X, Jenkins, CW

Mol Biol Cell 1996
8259215 A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4

Hannon, GJ, Serrano, M, Beach, D

Nature 1993
9190208 Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation

Connell-Crowley, L, Goodrich, DW, Harper, JW

Mol Biol Cell 1997
11719808 The E2F1-3 transcription factors are essential for cellular proliferation

Nevins, JR, Maiti, B, Chong, GT, Leone, G, Sang, L, Wu, L, Saavedra, HI, Nuckolls, F, Wright, FA, Giangrande, P, Robinson, ML, Greenberg, ME, Orkin, S, Field, SJ, Timmers, C

Nature 2001
8497257 Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression

Hiebert, SW

Mol. Cell. Biol. 1993
7859739 Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product

Peters, G, Bates, S, Mann, DJ, Parry, D

EMBO J. 1995
1828393 The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F

Bagchi, S, Raychaudhuri, P, Weinmann, R

Cell 1991
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