DNA Replication Stalling Attenuates Tyrosine Kinase Signaling to Suppress S Phase Progression

Cancer Cell. 2008 Aug 12;14(2):166-79. doi: 10.1016/j.ccr.2008.06.003.

Abstract

Here we report that T cell protein tyrosine phosphatase (TCPTP)-dependent and -independent pathways attenuate the JAK and Src protein tyrosine kinases (PTKs) and STAT3 phosphorylation to suppress cyclin D1 expression and S phase progression in response to DNA replication stress. Cells that lack TCPTP fail to suppress JAK1, Src, and STAT3, allowing for sustained cyclin D1 levels and progression through S phase despite continued replication stress. Cells that bypass the checkpoint undergo aberrant mitoses with lagging chromosomes that stain for the DNA damage marker gamma H2AX. Therefore, inactivating JAK, Src, and STAT3 signaling pathways in response to DNA replication stress may be essential for the suppression of S phase progression and the maintenance of genomic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Chromosomes, Mammalian / metabolism
  • Cyclin D1 / metabolism
  • DNA Replication*
  • Mice
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism*
  • S Phase*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*

Substances

  • Cell Cycle Proteins
  • STAT3 Transcription Factor
  • Cyclin D1
  • Atr protein, mouse
  • Protein-Tyrosine Kinases
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2