Cancer Letters

Cancer Letters

Volume 171, Issue 1, 28 August 2001, Pages 1-10
Cancer Letters

Mini-review
Ras and Rho regulation of the cell cycle and oncogenesis

https://doi.org/10.1016/S0304-3835(01)00528-6Get rights and content

Abstract

The important contribution of aberrant Ras activation in oncogenesis is well established. Our knowledge of the signaling pathways that are regulated by Ras is considerable. However, the number of downstream effectors of Ras continues to increase and our understanding of the role of these effector signaling pathways in mediating oncogenesis is far from complete and continues to evolve. Similarly, our understanding of the components that control mitogen-stimulated cell cycle progression is also very advanced. Where our understanding has lagged has been the delineation of the mechanism by which Ras causes a deregulation of cell cycle progression to promote the uncontrolled proliferation of the cancer cell. In this review, we summarize our current knowledge of how deregulated Ras activation alters the function of cyclin D1, p21Cip1, and p27Kip1. The two themes that we have emphasized are the involvement of Rho small GTPases in cell cycle regulation and the cell-type differences in how Ras signaling interfaces with the cell cycle machinery.

Introduction

The involvement of Ras proteins in cell signaling and in regulation of cell proliferation is well-established. Our knowledge of the signaling pathways that are regulated by Ras is considerable. Ras functions as a nodal point, where it is activated by diverse extracellular stimuli. Once activated, Ras in turn interacts with a diverse spectrum of effectors and initiates a multitude of cytoplasmic signaling cascades. Similarly, our understanding of the components that control mitogen-stimulated passage through G1 and entry into S phase of the cell cycle is also very advanced. A regulation of the activity of positive and negative regulatory proteins that control the activity of the Rb tumor suppressor protein dictates G1 progression. Where our understanding has lagged has been the delineation of the mechanism by which Ras causes a deregulation of cell cycle progression to promote the uncontrolled proliferation of the cancer cell. Recent studies have begun to establish the links between Ras signaling pathways and cell cycle regulatory proteins. One important theme that has emerged is that the Ras-related Rho GTPases may facilitate this regulation. A second theme involves cell-type differences in how Ras signaling interfaces with the cell cycle machinery. Recent excellent reviews summarize our current understanding of Ras signaling [1], [2], [3], cell cycle regulation [4], [5], or both [6], [7], [8]. The focus of this review will be on the recent advances made from the study of Ras and Rho small GTPases and the signaling mechanisms that connect them with the cell cycle regulatory machinery.

Section snippets

Ras and signal transduction

Ras proteins are positioned at the inner face of the plasma membrane where they serve as relay switches to transmit extracellular signal-mediated stimuli to cytoplasmic signaling cascades [9]. Ras proteins function as GDP/GTP-regulated switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Mitogenic signals stimulate a transient formation of active GTP-bound Ras and activated Ras in turn interacts with downstream effector targets. This activation is facilitated

Regulation of the Rb pathway: a requirement for Ras

Mitogenic stimuli promote the entry of quiescent cells into the first gap phase (G1) and initiation of DNA synthesis (S phase) of the cell cycle [4]. Exit from or entry into the G0 quiescent state is controlled by positive and negative regulatory proteins. G1 cyclin-dependent kinases (CDKs) serve as positive regulators. D-type cyclins (D1, D2, D3) complex with CDK4 and CDK6 to stimulate their kinase activities, which in turn cause the phosphorylation and inactivation of the retinoblastoma (Rb)

Ras and Cyclin D1

Perhaps the best-characterized component of the cell cycle machinery targeted by Ras is cyclin D1 [6], [7], [8]. Cyclin D1 is induced transcriptionally in response to growth factor stimulation [33]. Cyclin D1 transcription and protein expression is typically elevated by mid-G1, associated with the second peak of Ras activation [24], with maximal accumulation occurring closer to the G1/S boundary. Cyclin D1 is rapidly degraded, so its expression is dependent on continued growth factor

Ras and p21Cip1

The levels of p21 are low in serum-starved or density-arrested quiescent cells and mitogenic stimuli that activate the Ras/ERK pathway induce expression of p21Cip1 protein [51], [52] (Fig. 1). However, the majority of observations suggest that p21Cip1 antagonizes Ras growth stimulation. For example, three groups found that expression of low levels of activated Ras or Raf to be mitogenic for NIH 3T3 or schwann cells, but high levels of activated Ras or Raf caused cell cycle arrest that was

Ras and p27Kip1

A link between Ras and a second CDK inhibitor p27Kip1, where Ras causes downregulation of p27 expression, has also been observed in a variety of cell types. p27Kip1 protein levels exhibit a pattern of expression that is opposite that of p21Cip1 [62]. p27Kip1 levels are elevated in quiescent cells, increased by stimuli that cause growth arrest, and downregulated in response to mitogenic stimuli via a Ras-dependent mechanism [34], [63]. In contrast to p21Cip1, p27Kip1 mRNA levels are constant

Rho GTPases and cell cycle regulation

Rho GTPases constitute a major branch of the Ras superfamily of small GTPases [30], [71], [72]. To date, at least 18 mammalian Rho GTPases have been identified, with RhoA, Rac1, and Cdc42 being the most intensely studied. Like Ras, Rho GTPases function as regulated GDP/GTP switches that are activated by diverse extracellular stimuli that stimulate G protein-coupled receptors, receptor tyrosine kinases, integrins, and other cell surface receptors. Once activated, each Rho GTPase interacts with a

Concluding remarks

The mechanism by which aberrant Ras and Rho GTPase activation promotes oncogenesis clearly involves a deregulation of cell cycle progression. Much is now known regarding how Ras and Rho signaling can control both positive (cyclin D1) and negative (p21Cip1 and p27Kip1) regulators to facilitate exit from G0, progression through G1, and initiation of DNA synthesis. However, despite being a topic of intense research study, the precise consequences of oncogenic Ras and Rho activation on these

Acknowledgements

We thank Misha Rand for assistance in manuscript preparation. Our studies were supported by from the National Institutes of Health to C.J.D. (CA42978, CA55008 and CA63071). K.P. was supported by fellowships from the National Science Foundation and UNCF-Merck.

References (85)

  • K. Pruitt et al.

    Ras inactivation of the retinoblastoma pathway by distinct mechanisms in NIH 3T3 fibroblast and RIE-1 epithelial cells

    J. Biol. Chem.

    (2000)
  • S. Aznar et al.

    Rho signals to cell growth and apoptosis

    Cancer Lett.

    (2001)
  • M. Hitomi et al.

    Ras-dependent cell cycle commitment during G2 phase

    FEBS Lett.

    (2001)
  • H. Matsushime et al.

    Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle

    Cell

    (1991)
  • V. Nancy et al.

    Identification and characterization of potential effector molecules of the Ras-related GTPase Rap2

    J. Biol. Chem.

    (1999)
  • J. Shao et al.

    Oncogenic Ras-mediated cell growth arrest and apoptosis is associated with increased ubiquitin-dependent cyclin D1 degradation

    J. Biol. Chem.

    (2000)
  • J.N. Lavoie et al.

    Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway

    J. Biol. Chem.

    (1996)
  • C. Albanese et al.

    Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions

    J. Biol. Chem.

    (1995)
  • R.C. Muise-Helmericks et al.

    Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway

    J. Biol. Chem.

    (1998)
  • S.W. Blain et al.

    Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4

    J. Biol. Chem.

    (1997)
  • H. Greulich et al.

    An analysis of Mek1 signaling in cell proliferation and transformation

    J. Biol. Chem.

    (1998)
  • A. Vogt et al.

    The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21WAF1/CIP1/SDI1 in a p53-independent manner

    J. Biol. Chem.

    (1997)
  • J.K. Westwick et al.

    Transforming potential of Dbl family proteins correlates with transcription from the cyclin D1 promoter but not with activation of Jun NH2-terminal kinase, p38/Mpk2, serum response factor or c-Jun

    J. Biol. Chem.

    (1998)
  • D. Joyce et al.

    Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway

    J. Biol. Chem.

    (1999)
  • O. Gjoerup et al.

    Rac and Cdc42 are potent stimulators of E2F-dependent transcription capable of promoting retinoblastoma susceptibility gene product hyperphosphorylation

    J. Biol. Chem.

    (1998)
  • J.D. Weber et al.

    Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27

    J. Biol. Chem.

    (1997)
  • W. Hu et al.

    RhoA stimulates p27(Kip) degradation through its regulation of cyclin E/CDK2 activity

    J. Biol. Chem.

    (1999)
  • A. Hirai et al.

    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.

    (1997)
  • S. Aznar et al.

    Rho signals to cell growth and apoptosis

    Cancer Lett.

    (2001)
  • S.L. Campbell et al.

    Increasing complexity of Ras signaling

    Oncogene

    (1998)
  • J.M. Shields et al.

    Understanding Ras: ‘it ain't over ‘til it's over’

    Trends Cell Biol.

    (2000)
  • C.J. Sherr et al.

    positive and negative regulators of G1-phase progression

    Genes Dev.

    (1999)
  • J.W. Harbour et al.

    The Rb/E2F pathway: expanding roles and emerging paradigms

    Genes Dev.

    (2000)
  • E. Kerkhoff et al.

    Cell cycle targets of Ras/Raf signalling

    Oncogene

    (1998)
  • M.S. Boguski et al.

    Proteins regulating Ras and its relatives

    Nature

    (1993)
  • M. Barbacid

    ras genes

    Annu. Rev. Biochem.

    (1987)
  • G.J. Clark et al.

    Oncogenic activation of Ras proteins. In: GTPases in Biology I

  • G.G. Kelley et al.

    Phospholipase C(epsilon): a novel Ras effector

    EMBO J.

    (2001)
  • L.S. Mulcahy et al.

    Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells

    Nature

    (1985)
  • L.A. Feig et al.

    Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP

    Mol. Cell. Biol.

    (1988)
  • H. Cai et al.

    Effect of a dominant inhibitory Ha-ras mutation o mitogenic signal transduction in NIH 3T3 cells

    Mol. Cell. Biol.

    (1990)
  • S. Dobrowolski et al.

    Cellular ras activity is required for passage through multiple points of the G0/G1 phase in the BALB/c 3T3 cells

    Mol. Cell. Biol.

    (1994)
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