ATM is upregulated during the mitogenic response in peripheral blood mononuclear cells

Patients with the human genetic disorder ataxia-telangiectasia (A-T) are ch aracterized by immunodeficiency and a predisposition to develop lymphoid ma lignancies. The gene mutated in A-T patients, ATM codes for a high molecula r weight protein that is implicated in DNA damage recognition and cell cycl e control. The ATM protein does not change in amount or cellular distributi on throughout the cell cycle or in response to DNA damaging agents. Because peripheral blood mononuclear cells (PBMCs) are largely in a state of quies cence and can be readily stimulated to enter a proliferative phase and beca use A-T cells exhibit growth abnormalities and senescence, indicative of a general intracellular defect in signalling, we chose PBMCs to examine the r elationship of ATM to the proliferative status of the cell. We show here th at ATM protein is present at low levels in freshly isolated PBMCs and incre ases approximately 6-fold to 10-fold in response to a mitogenic stimulus, r eaching a maximum after 3 to 4 days. A similar, but delayed response, was e vident in the presence of serum only, This increase in ATM protein was acco mpanied by an increase in ATM kinase activity, While expression of ATM prot ein increased during proliferation, ATM mRNA expression was unchanged in st imulated and unstimulated cells and there was no evidence for increased ATM protein stability in the phytohemagglutinin (PHA)-treated cells. In keepin g with the reduced levels of ATM in quiescent cells, the extent of radiatio n-induction of the p53 pathway was significantly lower than in mitogen-stim ulated cells. Basal levels of p21 were elevated in quiescent cells, and the response to radiation was negligible or reduced compared with proliferatin g cells over a P-hour period, Overall, the data suggest that the increase i n ATM protein in proliferating cells is due to posttranscriptional regulati on and points to a role for ATM in more general signalling. (C) 1999 by The American Society of Hematology.