Rapamycin resistance in ataxia-telangiectasia

Heather Beamish, Richard Williams, Philip Chen, Kum Kum Khanna, Karen Hobson, Dianne Watters, Yosef Shiloh, Martin Lavin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The gene mutated in the human genetic disorder ataxiatelangiectasia (A-T) has been described recently and the complete coding sequence of this gene, ATM, has been reported. The derived amino acid sequence demonstrates significant homologies to several proteins containing a phosphatidylinositol 3-kinase (PI3-kinase) domain, including the yeast TOR proteins and the human protein FRAP. Since the TOR and FRAP proteins are targets for the immunosuppressive drug rapamycin, we have investigated the effects of this compound on A-T cells. We report here that 3 A-T cell lines are more resistant than control cells to rapamycin's growth inhibiting effects but were more sensitive to the PI3-kinase inhibitor wortmannin. As expected rapamycin (1 nM) inhibited the rate of exit of control cells from G1 phase but failed to perturb the progression of A-T cells. This difference in cell cycle progress after rapamycin treatment is reflected in ribosomal S6 protein kinase (p70(S6k)) by both a downward mobility shift on SDS-PAGE and inhibition of activity. Furthermore, the G1 phase cyclin-dependent kinase, cyclin E-cdk2, was rapidly inhibited in control cells post-treatment, whereas in A-T cells it took considerably longer to observe inhibition. There was no evidence that a GST-FKBP12 fusion protein specifically precipitated the ATM protein in the presence of rapamycin in either cell type. These results demonstrate that the ATM protein is not a direct target for rapamycin but its functional loss renders cells more resistant to this compound.

Original languageEnglish
Pages (from-to)963-970
Number of pages8
JournalOncogene
Volume13
Issue number5
StatePublished - 1996

Keywords

  • Ataxia-telangiectasia
  • Cell cycle
  • Cyclin kinase
  • Rapamycin
  • Wortmannin

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