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PMID: 9199319 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1.

Molecular and cellular biology ·Vol. 17 ·No. 7 ·1997-07-00 ·Pages 3850-7

Aktas H, Cai H, Cooper GM

Abstract

Activation of growth factor receptors by ligand binding initiates a cascade of events leading to cell growth and division. Progression through the cell cycle is controlled by cyclin-dependent protein kinases (Cdks), but the mechanisms that link growth factor signaling to the cell cycle machinery have not been established. We report here that Ras proteins play a key role in integrating mitogenic signals with cell cycle progression through G1. Ras is required for cell cycle progression and activation of both Cdk2 and Cdk4 until approximately 2 h before the G1/S transition, corresponding to the restriction point. Analysis of Cdk-cyclin complexes indicates that Ras signaling is required both for induction of cyclin D1 and for downregulation of the Cdk inhibitor p27KIP1. Constitutive expression of cyclin D1 circumvents the requirement for Ras signaling in cell proliferation, indicating that regulation of cyclin D1 is a critical target of the Ras signaling cascade.

MeSH Terms
3T3 Cells Animals CDC2-CDC28 Kinases Cell Cycle Cell Cycle Proteins Cyclin D1 Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/physiology Cyclins/metabolism Enzyme Activation Mice Microtubule-Associated Proteins/metabolism Oncogene Proteins/metabolism Protein Serine-Threonine Kinases/physiology Proto-Oncogene Proteins/physiology Proto-Oncogene Proteins c-raf Proto-Oncogene Proteins p21(ras)/physiology Signal Transduction Tumor Suppressor Proteins
Chemicals
Cdkn1b protein, mouse Cell Cycle Proteins Cyclins Microtubule-Associated Proteins Oncogene Proteins Proto-Oncogene Proteins Tumor Suppressor Proteins Cyclin D1 Cyclin-Dependent Kinase Inhibitor p27 Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-raf CDC2-CDC28 Kinases Cdk2 protein, mouse Cdk4 protein, mouse Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Aktas H
Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cai H
Cooper G M
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.7.3850
Published
1997-07-00
Pages
3850-7
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC232237
Subset
IM
Grants
NCI NIH HHS · R01 CA18689 · United States
External Links
PubMed source DOI: 10.1128/MCB.17.7.3850 PMC Full Text View journal details
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