Mitogen-activated protein (MAP) kinases, p42MAPK and p44MAPK, are central components of growth-promoting signalling pathways. However, how stimulation of MAP kinases culminates in cell-cycle progression is still poorly understood. Here we show that mitogenic stimulation of NIH 3T3 cells causes a sustained activation of MAP kinases, which lasts until cells begin progressing through the G1/S boundary. Furthermore, we observed that disruption of the MAP-kinase pathway with a selective MEK (MAP kinase/extracellular-signal-regulated protein kinase kinase) inhibitor, PD98059, prevents the activation of cyclin-dependent kinase (Cdk) 2 and DNA synthesis, even when added during late G1 phase, once the known mechanisms by which MAP kinase controls G1 progression, accumulation of G1 cyclins and degradation of Cdk inhibitors have already taken place. Moreover, we provide evidence indicating that MAP kinases control Cdk2 Thr-160 activating phosphorylation and function, possibly by regulating the activity of a Cdk-activating kinase, thus promoting the re-initiation of DNA synthesis. These findings suggest the existence of a novel mechanism whereby signal-transducing pathways converging on MAP kinases can affect the cell-cycle machinery and, ultimately, participate in cell-growth control.
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Research Article|
July 25 2000
Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G1 phase
Mario CHIARIELLO;
Mario CHIARIELLO
1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Building 30, Room 211, Bethesda, MD 20892-4330, U.S.A.
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Eliana GOMEZ;
Eliana GOMEZ
1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Building 30, Room 211, Bethesda, MD 20892-4330, U.S.A.
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J. Silvio GUTKIND
J. Silvio GUTKIND
1
1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Building 30, Room 211, Bethesda, MD 20892-4330, U.S.A.
1To whom correspondence should be addressed (e-mail gutkind@dir.nidcr.nih.gov).
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Publisher: Portland Press Ltd
Received:
April 27 2000
Accepted:
June 01 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 349 (3): 869–876.
Article history
Received:
April 27 2000
Accepted:
June 01 2000
Citation
Mario CHIARIELLO, Eliana GOMEZ, J. Silvio GUTKIND; Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G1 phase. Biochem J 1 August 2000; 349 (3): 869–876. doi: https://doi.org/10.1042/bj3490869
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