Expression of the v-Src oncoprotein in fibroblasts disrupts normal regulation of the CDK inhibitor p27 and inhibits quiescence

D Johnson, M C Frame, J A Wyke

Research output: Contribution to journalArticlepeer-review

Abstract

To determine how an oncogenic tyrosine kinase disturbs cell cycle control we examined expression of cell cycle proteins and growth of fibroblasts reversibly transformed by a temperature sensitive mutant of v-Src (ts LA 29). ts LA 29 Rat-1 cells and normal Rat-1 cells had similar growth rates but the transformed cells traversed the G1 phase of the cell cycle more rapidly and failed to exit cycle efficiently in response to serum starvation and cell confluence. Cyclin D1 and cyclin E levels were not elevated in growing ts LA 29 Rat-1 cells and the abbreviated G1 was further accelerated by overexpression of cyclin E. A fall in cyclin E and cyclin A dependent kinase activities in Rat-1 cells in response to inhibitory growth conditions was abrogated in ts LA 29 Rat-1 cells and correlated with lack of p27 accumulation or cyclin A down regulation, the latter due to sustained cyclin A promoter activity. The expression of p27 mRNA was lower in ts LA 29 Rat-1 cells than Rat-1 cells and was elevated following v-Src inactivation concurrent with an increase in p27 promoter activity and temporary cell cycle exit. The suppression of mRNA or transcription is a novel way an oncoprotein can induce down regulation of p27 and contributes to the G1 shortening and perturbed cell cycle regulation of the v-Src transformed cells.
Original languageEnglish
Pages (from-to)2017-28
Number of pages12
JournalOncogene
Volume16
Issue number15
DOIs
Publication statusPublished - 16 Apr 1998

Keywords

  • Animals
  • Cell Cycle Proteins
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases
  • Cyclins
  • Enzyme Inhibitors
  • G1 Phase
  • Microtubule-Associated Proteins
  • Oncogene Protein pp60(v-src)
  • Rats
  • Transcription, Genetic
  • Tumor Suppressor Proteins

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