Defect in radiation signal transduction in ataxia-telangiectasia.
Exposure of mammalian cells to ionizing radiation causes a delay in progression through the cycle at several checkpoints. Cells from patients with ataxia-telangiectasia (A-T) ignore these checkpoint controls postirradiation. The tumour suppressor gene product p53 plays a key role at the G1/S checkpoint preventing the progression of cells into S phase. The induction of p53 by radiation is reduced and/or delayed in A-T cells, which appears to account for the failure of delay at the G1/S checkpoint. We have investigated further this defect in radiation signal transduction in A-T. While the p53 response was defective after radiation, agents that interfered with cell cycle progression such as mimosine, aphidicolin and deprivation of serum led to a normal p53 response in A-T cells. None of these agents caused breaks in DNA, as determined by pulse-field gel electrophoresis, in order to elicit the response. Since this pathway is mediated by protein kinases, we investigated the activity of several of these enzymes in control and A-T cells. Ca+2-dependent and -independent protein kinase C activities were increased by radiation to the same extent in the two cell types, a variety of serine/threonine protein kinase activities were approximately the same and anti-tyrosine antibodies failed to reveal any differences in protein phosphorylation between A-T and control cells. It is not evident what is the nature of the defect in signal transduction in A-T cells. However, it is clear that the p53 response is normal in these cells after exposure to some agents and it is mediated through protein kinase C or another serine/threonine kinase.
Lavin
M F
MF
Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, Bancroft Centre, Brisbane, Australia.
Khanna
K K
KK
Beamish
H
H
Teale
B
B
Hobson
K
K
Watters
D
D
D001260:Ataxia Telangiectasia / Q000473:pathology* / Q000503:physiopathology*; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage; D005347:Fibroblasts / Q000528:radiation effects; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects; D009281:Naphthalenes; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology* / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects
D009281:Naphthalenes; D011083:Polycyclic Compounds; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; C058819:calphostin C