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.
As RAS mutations are among the most frequent alterations in human cancers, RAS proteins and their signalling pathways have been studied intensively. Here, we outline the contributions of H-RAS, N-RAS and K-RAS to cell-cycle progression and cell growth. We also summarize recent results that indicate how other members of the RAS-GTPase subfamily — including E-RAS, RHEB, R-RAS, TC21 and RAL, as well as RHO GTPases — promote proliferation by regulating the transcription, translation and degradation of key cell-cycle components.
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We apologize to our colleagues whose work could not be cited because of space restrictions. Work in the Olson laboratory is supported by the American Cancer Society and the National Institutes of Health. Research in the Marshall laboratory is supported by Cancer Research UK.
The authors declare no competing financial interests.
The state of a cell that has exited the cell cycle and is in the G0 ('resting') phase.
A protein containing a mutation that adversely affects the function of the corresponding, normal wild-type protein within the same cell. For small GTPases, dominant-negatives are inactive proteins with a reduced affinity for GTP that inhibit the wild-type proteins by binding and sequestering guanine-nucleotide-exchange factors.
- AP-1 SITE
The palindromic DNA sequence TGACTCA, which serves as a binding site for transcription-factor complexes formed from heterodimers of FOS- and JUN-family proteins.
A large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that incorporates the catalytic activity, and two regulatory 19S particles.
- FORKHEAD TRANSCRIPTION-FACTOR FAMILY
A family consisting of more than 40 members, which belong to the winged-helix class of DNA-binding proteins and are involved in diverse cellular functions, including glucose metabolism, apoptosis and cell-cycle regulation.
A domain found in the F-box family of proteins that binds and recruits protein substrates to SKP1/CUL1/F-box protein (SCF) E3 ubiquitin ligases. F-box proteins mediate the interaction between the substrate and the ubiquitin ligase, which results in substrate ubiquitylation and degradation by the proteasome.
- E3 UBIQUITIN LIGASE
The final enzyme complex in the ubiquitin-conjugation pathway. E3 enzymes transfer ubiquitin from previous components of the pathway to the substrate protein to form a covalently linked ubiquitin–substrate conjugate, which is then degraded by the proteasome.
Or polyribosome; two or more ribosomes attached to different points on the same strand of mRNA.
- TOP TRACTS
Terminal oligopyrimidine (TOP) tract. An uninterrupted sequence of 4–20 pyrimidines that is typically found in the 5′-untranslated region of messenger RNAs that encode components of the mammalian translational apparatus.
- GTPase-ACTIVATING PROTEIN
(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP-bound) to inactive (GDP-bound).
A genetic interaction between two alleles. Epistatic analysis studies the genetic interaction between gene products in a signalling pathway. By determining the phenotypes of single and double mutants, the functional order of the components can be inferred.
- RNA INTERFERENCE
The use of double-stranded RNAs, with sequences that precisely match a given gene, to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.
A structural loop that is highly conserved in the catalytic domains of protein kinases. Phosphorylation of this transactivation loop is often required for full catalytic activity.
A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as RAS GTPases, that contain a carboxy-terminal CAAX motif. Farnesylation promotes attachment of the modified proteins to membranes.
- STRESS FIBRES
A component of the actin cytoskeleton that consists of contractile bundles of actin and myosin II, which terminate in adhesion plaques that link the actin cytoskeleton to the cell surface. Stress fibres are involved in cell adhesion and the generation of tensile force.
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Coleman, M., Marshall, C. & Olson, M. RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol 5, 355–366 (2004). https://doi.org/10.1038/nrm1365
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