title: Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression.
abstract: Bcl-2 can both promote and attenuate tumorigenesis. Although the former function is relatively well characterized, the mechanism of the latter remains elusive. We report here that enforced Bcl-2 expression in MCF7 cells stabilizes p53, induces phosphorylation of p53 serine 15 (p53pSer15) and inhibits MCF7 cell growth. Consistent with p53 Ser15 being a target of ataxia telangiectasia mutated protein(ATM)/ATR (ATM- and rad3-related) in the DNA damage response, Bcl-2 activates ATM by inducing ATM Ser1981 phosphorylation, which is accompanied with the phosphorylaton of two additional ATM substrates, Chk2 Thr68 and H2AX Ser139. Downregulation of ATM using a specific small interference RNA fragment (ATMRNAi) abolished Bcl-2-induced p53pSer15 and Bcl-2-mediated growth inhibition of MCF7 cells. Ectopic expression of a dominant-negative p53 mutant, p53175H, partially rescued this growth inhibition. Taken together, these observations demonstrate the contribution of ATM-p53 function to Bcl-2-mediated inhibition of MCF7 cell growth, indicating an ATM-mediated surveillance system for regulating Bcl-2 overexpression. Consistent with this concept, we found that MCF7 cells express Bcl-2 heterogeneously with 34.5% of cells being Bcl-2 negative. In general, Bcl-2-positive MCF7 cells proliferate slower than those of Bcl-2 negative. Thus, we provide evidence suggesting that activation of ATM suppresses Bcl-2-induced tumorigenesis, and that attenuation of ATM function may be an important event in breast cancer progression.
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: J M
authors.initials: JM
authors.lastname: Lahti
authors.forename: A
authors.initials: A
authors.lastname: Bruce
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: K
authors.initials: K
authors.lastname: Parihar
authors.forename: C
authors.initials: C
authors.lastname: Fan
authors.forename: J
authors.initials: J
authors.lastname: Grenet
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: V J
authors.initials: VJ
authors.lastname: Kidd
authors.forename: S
authors.initials: S
authors.lastname: Cormier
authors.forename: D
authors.initials: D
authors.lastname: Tang
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases