title: ATM is upregulated during the mitogenic response in peripheral blood mononuclear cells.
abstract: 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.
authors.affiliation: Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan. toshi-gif@umin.u-tokyo.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Fukao
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.forename: G
authors.initials: G
authors.lastname: Birrell
authors.forename: M
authors.initials: M
authors.lastname: Gatei
authors.forename: H
authors.initials: H
authors.lastname: Tashita
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Cross
authors.forename: P
authors.initials: P
authors.lastname: Kedar
authors.forename: D
authors.initials: D
authors.lastname: Watters
authors.forename: K K
authors.initials: KK
authors.lastname: Khana
authors.forename: I
authors.initials: I
authors.lastname: Misko
authors.forename: N
authors.initials: N
authors.lastname: Kondo
authors.forename: M F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010835:Phytohemagglutinins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D010835:Phytohemagglutinins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C493956:CDKN1A protein, human; C576324:ATM protein, human