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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1998-2006
ATM Is Upregulated During the Mitogenic Response in Peripheral
Blood Mononuclear Cells
Toshiyuki Fukao,
Hideo Kaneko,
Geoff Birrell,
Magtouf Gatei,
Hideaki Tashita,
Toko Yoshida,
Simone Cross,
Padmini Kedar,
Dianne Watters,
Kum Kum Khana,
Ihor Misko,
Naomi Kondo, and
Martin F. Lavin
From the Department of Pediatrics, Gifu University School of
Medicine, Gifu, Japan; the Queensland Cancer Fund Research Unit, the
Queensland Institute of Medical Research, PO Royal Brisbane Hospital,
Herston, Brisbane, Australia; and the Department of Surgery, the
University of Queensland, PO Royal Brisbane Hospital, Herston,
Brisbane, Australia.
Patients with the human genetic disorder ataxia-telangiectasia (A-T)
are characterized by immunodeficiency and a predisposition to develop
lymphoid malignancies. The gene mutated in A-T patients, ATM,
codes for a high molecular weight protein that is implicated in DNA
damage recognition and cell cycle control. The ATM protein does not
change in amount or cellular distribution throughout the cell cycle or
in response to DNA damaging agents. Because peripheral blood
mononuclear cells (PBMCs) are largely in a state of quiescence and can
be readily stimulated to enter a proliferative phase and because A-T
cells exhibit growth abnormalities and senescence, indicative of a
general intracellular defect in signalling, we chose PBMCs to examine
the relationship of ATM to the proliferative status of the cell. We
show here that ATM protein is present at low levels in freshly isolated
PBMCs and increases approximately 6-fold to 10-fold in response to a
mitogenic stimulus, reaching a maximum after 3 to 4 days. A similar,
but delayed response, was evident in the presence of serum only. This
increase in ATM protein was accompanied by an increase in ATM kinase
activity. While expression of ATM protein increased during
proliferation, ATM mRNA expression was unchanged in stimulated
and unstimulated cells and there was no evidence for increased ATM
protein stability in the phytohemagglutinin (PHA)-treated cells. In
keeping with the reduced levels of ATM in quiescent cells, the extent
of radiation-induction of the p53 pathway was significantly lower than
in mitogen-stimulated cells. Basal levels of p21 were elevated in
quiescent cells, and the response to radiation was negligible or
reduced compared with proliferating cells over a 2-hour period.
Overall, the data suggest that the increase in ATM protein in
proliferating cells is due to posttranscriptional regulation and points
to a role for ATM in more general signalling.
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