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.
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Acknowledgements
We are grateful to Steve Coats, Amgen, USA for p27 cDNA; Gordon Peters, ICRF for p16 construct; Sybille Mittnacht, ICR, London for bacteria expressing GST-pRb-C, CST for antibody against phospho-T160 CDK2. D Riley was funded by Association for International Cancer Research project grant number 98284 and The Sylvia Aitkin Trust, NO Carragher and MC Frame were funded by the Cancer Research Campaign.
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Riley, D., Carragher, N., Frame, M. et al. The mechanism of cell cycle regulation by v-Src. Oncogene 20, 5941–5950 (2001). https://doi.org/10.1038/sj.onc.1204826
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DOI: https://doi.org/10.1038/sj.onc.1204826
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