The mechanism of cell cycle regulation by v-Src
- 20 September 2001
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 20 (42), 5941-5950
- https://doi.org/10.1038/sj.onc.1204826
Abstract
The tyrosine kinase oncoprotein v-Src can overcome the requirements for serum growth factors and anchorage which restrain normal cell growth. Here we investigated the biochemical mechanisms whereby v-Src induces quiescent cells to enter S phase in the absence of serum mitogens. Activating a temperature sensitive v-Src in quiescent cells sequentially induced cyclins D1, E and A and also down regulated p27. We addressed whether p27 down regulation was required to activate cyclin D1/CDK4/6 or cyclin E/CDK2 by engineering cells with inducible p27. Both S phase entry and activation of cyclin/CDKs were inhibited by over expression of p27. Using cells engineered with inducible p16 we showed that Cyclin D/CDK4/6 activity was required for v-Src to increase expression of cyclin A but not cyclin E. To determine which downstream kinases mediated these effects of v-Src we added pharmacological inhibitors of phosphatidylinositol 3-kinase (PI3-K), LY294002 or mitogen activated protein kinase kinase (MEK), U0126. PI3-K was required for v-Src to activate MEK and MEK was required for v-Src to increase expression of cyclins D1 and E. However, the MEK inhibitor prevented p27 protein down regulation whereas the PI3-K inhibitor did not. This was because reduced PI3-K activity lead to proteolytic degradation of p27.Keywords
This publication has 44 references indexed in Scilit:
- Forkhead Transcription Factor FKHR-L1 Modulates Cytokine-Dependent Transcriptional Regulation of p27KIP1Molecular and Cellular Biology, 2000
- Full Oncogenic Activities of v-Src Are Mediated by Multiple Signaling PathwaysPublished by Elsevier BV ,2000
- Regulation of both apoptosis and cell survival by the v-Src oncoproteinCell Death & Differentiation, 2000
- Complex Mechanisms Underlying Impaired Activation of Cdk4 and Cdk2 in Replicative Senescence: Roles of p16, p21, and Cyclin D1Experimental Cell Research, 1999
- Expression of the v-Src oncoprotein in fibroblasts disrupts normal regulation of the CDK inhibitor p27 and inhibits quiescenceOncogene, 1998
- New functional activities for the p21 family of CDK inhibitors.Genes & Development, 1997
- The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.Genes & Development, 1997
- Dephosphorylation of Cdk2 Thr 160 by the Cyclin-Dependent Kinase-Interacting Phosphatase KAP in the Absence of CyclinScience, 1995
- Both p16 and p21 Families of Cyclin-dependent Kinase (CDK) Inhibitors Block the Phosphorylation of Cyclin-dependent Kinases by the CDK-activating KinasePublished by Elsevier BV ,1995
- Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.Genes & Development, 1994