Influence of Ras and Rho proteins on G1/S transition
Harvey rat sarcoma viral oncogene homolog (H-Ras) activates G1/S transition and cell proliferation mainly by v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/Mitogen-activated protein kinase kinases 1/2 (MEK1/2)/ Mitogen-activated protein kinases 3/1 (ERK1/2) cascade , . ERK1 and ERK2 inhibit transducer of ERBB2, 1 (Tob1) (a suppressor of Cyclin D1 expression) by phosphorylation at Ser 152, Ser 154, and Ser 164, thus activating expression of Cyclin D1 and Mdm2 p53 binding protein homolog (MDM2) and G1/S progression .
Cyclin D1 forms active complexes with cyclin-dependent kinases CDK4 or CDK6. These complexes phosphorylate retinoblastoma (Rb) and inhibit its ability to suppress E2F1 transcription-factor. E2F1 induces the transcription of another Cyclins required for S-phase DNA synthesis, such as Cyclin E and Cyclin A2 , , .
Cyclin E forms a complex with CDK2 that also inhibits Rb and cyclin-dependent kinase inhibitor 1B (p27Kip1)by phosphorylation , .
Another pathway of H-Ras induction of Cyclin D1 expression is by activation of Phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologs(AKT(PKB)) .AKT(PKB) probably via activation of Conserved helix-loop-helix ubiquitous kinase (IKK-alpha) followed by phosphorylation of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA) induces v-rel reticuloendotheliosis viral oncogene homolog A (RelA(p65 NF-kB)). NF-kB p50/p65 complex is required for Cyclin D1 expression , .
Phosphorylation of CyclinD1 by Glycogen synthase kinase 3 beta (GSK3beta) results in the ubiquitylation and degradation of Cyclin D1. However, H-Ras by PI3K/ AKT(PKB) inhibits Glycogen synthase kinase 3 beta (GSK3beta) activity, thereby enhancing Cyclin-D1 protein stability .
Moreover H-Ras activates Ciclin D1 expression and cell proliferation by Ral guanine nucleotide dissociation stimulator-like 2 (RGL2)/ v-ral simian leukemia viral oncogene homolog A (RalA) pathway , .
In addition, H-Ras via Raf/ MEK/ ERK and PI3K/ AKT(PKB)/ GSK3beta pathways enhances the accumulation of v-myc myelocytomatosis viral oncogene homolog (c-Myc) activity that promotes G1-phase of the cell cycle.
Rho family GTPases Ras homolog gene family, member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1), and Cell division cycle 42 (CDC42) are each required for progression from G1 to S phase .
Rac1 and CDC42 activate p21 protein (Cdc42/Rac)-activated kinase 1(Pak1). Pak1 via IKKs-independent pathway activates NF-kB p50/p65 that promotes expression of Cyclin D1 , , . Possibly, Rac1 and CDC42 via Pak1 cooperate with c-Raf-1 to activate MEK1/ERK1/2 pathway and promote Cyclin D1 expression and G1 progression. Pak1 phosphorylates MEK1 on Ser298, a site important for binding of c-Raf-1 to MEK1 , , .
Another possible pathway of Rac1 in G1 progression is Mitogen-activated protein kinase kinase kinase 11 (MLK3(MAP3K11))/ Mitogen-activated protein kinase kinase 4 (MEK4(MAP2K4))/ Mitogen-activated protein kinase 8 (JNK1(MAPK8)) signaling , . JNK1(MAPK8) probably by activation of Activating transcription factor 2 (ATF-2) induces Cyclin D1 expression .
CDC42 through ribosomal protein S6 kinase, 70kDa, polypeptide 1 (p70S6 kinase1) induces Cyclin E expression and promotes G1 progression .
RhoA influence on G1/S transition by two distinct mechanisms.
Firstly, geranylgeranylation of RhoA by protein geranylgeranyltransferase type I (GGTase1) is essential for repression of Cyclin-dependent kinase inhibitor 1A (p21) and p27Kip1 , , . RhoA via Diaphanous homolog 1 (DIA1) increases expression of mRNA and protein levels S-phase kinase-associated protein 2 (Skp2). Skp2 promotes ubiquitin-mediated proteasomal degradation of p27Kip1 and restores G1 progression . Skp2 expression is upregulated by E2F1 via positive feedback loop . Rac1 via actin polymerization also increases Skp2 levels and thus controls vascular smooth muscle cell proliferation . In addition, RhoA inhibits p21 expression , , .
Secondly, RhoA regulates expression of Cyclin D1 and Cyclin E , , . RhoA activates Rho-associated, coiled-coil containing protein kinase 2 (ROCK2). ROCK2 via phosphorylation of LIM domain kinases 2 (LIMK2) and inactivation the Myosin light chain phosphatase (MLCP), enhances phosphorylation of Myosin, light chain, regulatory (MRLC) by Myosin light chain kinase (MLCK). This leads to stress fiber formation , , consequent clustering of alpha-5/beta-1 integrin and Focal adhesion kinase (FAK1) phosphorylation, followed by activation of H-Ras/ c-Raf-1/MEK1(MAP2K1), MEK2(MAP2K2)/ ERK1/2 pathway, leading to the elevation of Cyclin D1 . Also phosphorylation of LIMK2 increases Cyclin A2 expression .
In addition, RhoA via ROCK2 and DIA1 activates signal transducer and activator of transcription 3 (STAT3) by phosphorylation of Tyr-705 and Ser-727 that accompanied STAT3 nuclear translocation. STAT3 induces NF-kB and Cyclin D1 transcription and is involved in NF-kB nuclear translocation .
- Kerkhoff E, Rapp UR
Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Molecular and cellular biology 1997 May;17(5):2576-86
- Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR
Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes & development 2000 Oct 1;14(19):2501-14
- Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T
Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes & development 2002 Jun 1;16(11):1356-70
- Gille H, Downward J
Multiple ras effector pathways contribute to G(1) cell cycle progression. The Journal of biological chemistry 1999 Jul 30;274(31):22033-40
- Welsh CF
Rho GTPases as key transducers of proliferative signals in g1 cell cycle regulation. Breast cancer research and treatment 2004 Mar;84(1):33-42
- Coleman ML, Marshall CJ, Olson MF
RAS and RHO GTPases in G1-phase cell-cycle regulation. Nature reviews. Molecular cell biology 2004 May;5(5):355-66
- Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE
Cyclin E-CDK2 is a regulator of p27Kip1. Genes & development 1997 Jun 1;11(11):1464-78
- Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr
NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Molecular and cellular biology 1999 Aug;19(8):5785-99
- Joyce D, Bouzahzah B, Fu M, Albanese C, D'Amico M, Steer J, Klein JU, Lee RJ, Segall JE, Westwick JK, Der CJ, Pestell RG
Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway. The Journal of biological chemistry 1999 Sep 3;274(36):25245-9
- Diehl JA, Cheng M, Roussel MF, Sherr CJ
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes & development 1998 Nov 15;12(22):3499-511
- Wolthuis RM, de Ruiter ND, Cool RH, Bos JL
Stimulation of gene induction and cell growth by the Ras effector Rlf. The EMBO journal 1997 Nov 17;16(22):6748-61
- Olson MF, Ashworth A, Hall A
An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science (New York, N.Y.) 1995 Sep 1;269(5228):1270-2
- Frost JA, Swantek JL, Stippec S, Yin MJ, Gaynor R, Cobb MH
Stimulation of NFkappa B activity by multiple signaling pathways requires PAK1. The Journal of biological chemistry 2000 Jun 30;275(26):19693-9
- Balasenthil S, Sahin AA, Barnes CJ, Wang RA, Pestell RG, Vadlamudi RK, Kumar R
p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. The Journal of biological chemistry 2004 Jan 9;279(2):1422-8
- Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE, Cobb MH
Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. The EMBO journal 1997 Nov 3;16(21):6426-38
- Hirsch E, Barberis L, Brancaccio M, Azzolino O, Xu D, Kyriakis JM, Silengo L, Giancotti FG, Tarone G, Fässler R, Altruda F
Defective Rac-mediated proliferation and survival after targeted mutation of the beta1 integrin cytodomain. The Journal of cell biology 2002 Apr 29;157(3):481-92
- Klein EA, Campbell LE, Kothapalli D, Fournier AK, Assoian RK
Joint requirement for Rac and ERK activities underlies the mid-G1 phase induction of cyclin D1 and S phase entry in both epithelial and mesenchymal cells. The Journal of biological chemistry 2008 Nov 7;283(45):30911-8
- Lambert JM, Karnoub AE, Graves LM, Campbell SL, Der CJ
Role of MLK3-mediated activation of p70 S6 kinase in Rac1 transformation. The Journal of biological chemistry 2002 Feb 15;277(7):4770-7
- Chou MM, Masuda-Robens JM, Gupta ML
Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression. The Journal of biological chemistry 2003 Sep 12;278(37):35241-7
- Hirai A, Nakamura S, Noguchi Y, Yasuda T, Kitagawa M, Tatsuno I, Oeda T, Tahara K, Terano T, Narumiya S, Kohn LD, Saito Y
Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells. The Journal of biological chemistry 1997 Jan 3;272(1):13-6
- Allal C, Favre G, Couderc B, Salicio S, Sixou S, Hamilton AD, Sebti SM, Lajoie-Mazenc I, Pradines A
RhoA prenylation is required for promotion of cell growth and transformation and cytoskeleton organization but not for induction of serum response element transcription. The Journal of biological chemistry 2000 Oct 6;275(40):31001-8
- Liberto M, Cobrinik D, Minden A
Rho regulates p21(CIP1), cyclin D1, and checkpoint control in mammary epithelial cells. Oncogene 2002 Feb 28;21(10):1590-9
- Mammoto A, Huang S, Moore K, Oh P, Ingber DE
Role of RhoA, mDia, and ROCK in cell shape-dependent control of the Skp2-p27kip1 pathway and the G1/S transition. The Journal of biological chemistry 2004 Jun 18;279(25):26323-30
- Assoian RK, Yung Y
A reciprocal relationship between Rb and Skp2: implications for restriction point control, signal transduction to the cell cycle and cancer. Cell cycle (Georgetown, Tex.) 2008 Jan 1;7(1):24-7
- Bond M, Wu YJ, Sala-Newby GB, Newby AC
Rho GTPase, Rac1, regulates Skp2 levels, vascular smooth muscle cell proliferation, and intima formation in vitro and in vivo. Cardiovascular research 2008 Nov 1;80(2):290-8
- Sahai E, Olson MF, Marshall CJ
Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. The EMBO journal 2001 Feb 15;20(4):755-66
- Tanaka T, Tatsuno I, Noguchi Y, Uchida D, Oeda T, Narumiya S, Yasuda T, Higashi H, Kitagawa M, Nakayama K, Saito Y, Hirai A
Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression. The Journal of biological chemistry 1998 Oct 9;273(41):26772-8
- Welsh CF, Roovers K, Villanueva J, Liu Y, Schwartz MA, Assoian RK
Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nature cell biology 2001 Nov;3(11):950-7
- Swant JD, Rendon BE, Symons M, Mitchell RA
Rho GTPase-dependent signaling is required for macrophage migration inhibitory factor-mediated expression of cyclin D1. The Journal of biological chemistry 2005 Jun 17;280(24):23066-72
- Croft DR, Olson MF
The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Molecular and cellular biology 2006 Jun;26(12):4612-27
- Roovers K, Assoian RK
Effects of rho kinase and actin stress fibers on sustained extracellular signal-regulated kinase activity and activation of G(1) phase cyclin-dependent kinases. Molecular and cellular biology 2003 Jun;23(12):4283-94
- Debidda M, Wang L, Zang H, Poli V, Zheng Y
A role of STAT3 in Rho GTPase-regulated cell migration and proliferation. The Journal of biological chemistry 2005 Apr 29;280(17):17275-85