The mechanism of cell cycle regulation by v-Src

D Riley, N O Carragher, M C Frame, J A Wyke

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)5941-50
Number of pages10
JournalOncogene
Volume20
Issue number42
DOIs
Publication statusPublished - 20 Sep 2001

Keywords

  • Animals
  • Butadienes
  • Cell Cycle
  • Cell Line
  • Cyclin A
  • Cyclin D1
  • Cyclin E
  • Cyclin-Dependent Kinases
  • Down-Regulation
  • Enzyme Inhibitors
  • Kinetics
  • MAP Kinase Kinase 1
  • Microfilament Proteins
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Muscle Proteins
  • Nitriles
  • Oncogene Protein pp60(v-src)
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger
  • Rats
  • Transfection

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