TY - JOUR AU - Olson, Michael F. AB - H-RAS, N-RAS and K-RAS GTPases promote cell-cycle progression through the RAF–MEK–ERK/MAPK, RAL and PI3K signalling pathways. Additional RAS-family members, including E-RAS, R-RAS, TC21 and RAL proteins, also promote cell-cycle progression and proliferation using these RAS-regulated pathways. The principal function of RAS in G1–S-phase progression is to inactivate the retinoblastoma (RB) protein and thereby relieve cells from its growth-inhibitory effects — cells without RB no longer require RAS activity. Cyclin-D1 induction is one of the key events required for RB phosphorylation and consequent G1-phase progression. Growth-factor-induced transcription of the cyclin-D1 gene, stabilization of the cyclin-D1 protein and formation of complexes containing cyclin D1 and cyclin-dependent kinase (CDK)4 or CDK6 is regulated primarily through RAS-dependent pathways. Mitogen-induced downregulation of the CDK inhibitor p27KIP1 is mediated by RAS through transcriptional and post-transcriptional mechanisms. Mitogens also signal through RAS to elevate p21CIP1 to moderate levels that allow p21CIP1 to promote the assembly, nuclear retention and stability of cyclin-D1–CDK complexes. Similar to RAS proteins, RHO GTPases contribute to cell-cycle progression by influencing the levels of cyclin D1 and of the CDK inhibitors p27KIP1 and p21CIP1. Mitogenic stimulation leads to enhanced rates of mRNA translation and synthesis of proteins that are required for cell growth and G1-phase progression. RAS and RHO signalling pathways are intimately involved in transducing mitogenic signals to the translational apparatus. RAS effector pathways converge on the tuberous sclerosis (TSC) complex, an inhibitor of the RAS-related RAS homologue enriched in brain (RHEB) GTPase. Inhibition of the TSC complex by these signalling pathways allows RHEB to activate the master translation regulator, target of rapamycin (TOR). Elevated protein translation promotes cell growth and proliferation. TI - RAS and RHO GTPases in G1-phase cell-cycle regulation JF - Nature Reviews Molecular Cell Biology DO - 10.1038/nrm1365 DA - 2004-05-01 UR - https://www.deepdyve.com/lp/springer-journals/ras-and-rho-gtpases-in-g1-phase-cell-cycle-regulation-PpC3VVwYV1 SP - 355 EP - 366 VL - 5 IS - 5 DP - DeepDyve ER -