Multiple Ras Effector Pathways Contribute to G1Cell Cycle Progression*
Abstract
The involvement of Ras in the activation of multiple early signaling pathways is well understood, but it is less clear how the various Ras effectors interact with the cell cycle machinery to cause G1 progression. Ras-mediated activation of extracellular-regulated kinase/mitogen-activated protein kinase has been implicated in cyclin D1 up-regulation, but there is little extracellular-regulated kinase activity during the later stages of G1, when cyclin D1 expression becomes maximal, implying that other effector pathways may also be important in cyclin D1 induction. We have addressed the involvement of Ras effectors from the phosphatidylinositol (PI) 3-kinase and Ral-GDS families in G1 progression and compared it to that of the Raf/mitogen-activated protein kinase pathway. PI 3-kinase activity is required for the expression of endogenous cyclin D1 and for S phase entry following serum stimulation of quiescent NIH 3T3 fibroblasts. Activated PI 3-kinase induces cyclin D1 transcription and E2F activity, at least in part mediated by the serine/threonine kinase Akt/PKB, and to a lesser extent the Rho family GTPase Rac. In addition, both activated Ral-GDS-like factor and Raf stimulate cyclin D1transcription and E2F activity and act in synergy with PI 3-kinase. Therefore, multiple cooperating pathways mediate the effects of Ras on progression through the cell cycle.
Footnotes
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↵* This work was supported by the Imperial Cancer Research Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported in part by an International Human Frontier Science Program Organization long-term fellowship. Current address: Dept. of Cardiovascular Biology, Genentech Inc., 460 Point San Bruno Blvd., South San Francisco, CA 94080.
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↵§ To whom correspondence should be addressed. Tel.: 44-171-269-3533; Fax: 44-171-269-3092; E-mail: downward@icrf.icnet.uk.
- Abbreviations:
- cdk
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cyclin-dependent kinase
- MAP
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mitogen-activated protein
- ERK
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extracellular-regulated kinase
- MEK
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MAP/ERK kinase
- PI
-
phosphatidylinositol
- PIP3
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PI 3,4,5-trisphosphate
- Rb
-
retinoblastoma
- Rlf
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Ral-GDS-like factor
- Ral-GDS
-
Ral guanine nucleotide dissociation stimulator
- PKB
-
protein kinase B
- TOR
-
target of rapamycin
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- Received January 13, 1999.
- Revision received April 26, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
