InfluenceofRasandRhoproteinsonG1toSTransition

The cell cycle transition from G1 to S phase is a key regulatory point in the cell cycle. This transition is regulated by the checkpoint kinase cdk2 that activates the G1 to S transition when it is associated with cyclin E. Cdk2/Cyclin E causes the G1 to S transition through phosphorylation of the tumor suppressor Rb, releasing the transcription factor E2F-1. Other pathways acting through Rac, Ras and Rho also regulate the G1 to S transition. Ras regulates cyclin D1 expression to affect the G1 to S transition. Transforming forms of Ras or Raf induce cyclin D1 expression and cause early entry into S phase. Signaling from Ras to Raf to MEK to ERKs induces Cyclin D1 expression, allowing Cyclin D1 to complex with Cdk4 and Cdk6 and phosphorylate Rb. Rac-1 and PAK appear to induce Cyclin D1 expression and induce the G1 to S transition primarily through activation of NF-kB to activate the Cyclin D1 promoter. Rho activates cdk2 and also inhibits p21 and p27 to induce cyclin D1 and stimulate the G1 to S transition. Rho represses p21 expression to block p21 induction by Ras and to allow Ras induced progression from G1 to S. Cells that lack p21 do not require Rho for Ras to induce cell cycle progression from G1 to S phase. The cooperative action of Ras, Rac and Rho to induce Cyclin D1 expression is a key component of oncogenic transformation.

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REFERENCES: Baldin, V. et al. (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev (5), 812-21 Dafna Bar-Sagi and Alan Hall. (2000) Ras and Rho GTPases: A Family Reunion. Cell, Vol. 103, 227-238 Frost, Jeffrey et al. (2000) Stimulation of NFkB Activity by Multiple Signaling Pathways Requires PAK1. J. Biol Chem 275(26):19693-99 Guttridge, D.C. et al. (1999) NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 19(8), 5785-99 Hirai, A. et al. (1997) 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. J Biol Chem. 272(1), 13-6. Kerkhoff, E., Rapp, U.R. (1997) Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol Cell Biol 17(5), 2576-86 Liberto, M., Cobrinik, D., Minden, A. (2002) Rho regulates p21(CIP1), cyclin D1, and checkpoint control in mammary epithelial cells. Oncogene 21(10), 1590-9 Tanaka, T. et al. (1998) 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. J Biol Chem. 273(41), 26772-8. Welsh, Catherine et al. (2001)Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nature Cell Bio vol 3; Nov 2001: 950-57