ATM is involved in cell-cycle control through the regulation of retinoblastoma protein phosphorylation.
Ataxia telangiectasia mutated protein (ATM) is a member of the phosphatidylinositol-3 kinase (PI3K) family, which has a role in the cellular response to DNA double-strand breaks (DSBs). In the present study, we evaluated the role of ATM in cell-cycle control in dopaminergic rat neuroblastoma B65 cells. For this purpose, ATM activity was either inhibited pharmacologically with the specific inhibitor KU-55933, or the ATM gene was partially silenced by transfection with small interfering RNA (siRNA). Our data indicate that although ATM inhibition did not affect the cell cycle, both treatments specifically decreased the levels of cyclin A and retinoblastoma protein (pRb), phosphorylated at Ser780. Furthermore, ATM inhibition decreased the active form of p53, which is phosphorylated at Ser15, and also decreased Bax and p21 expression. Using H(2)O(2) as a positive control of DSBs, caused a rapid pRb phosphorylation, this was prevented by KU-55933 and siRNA treatment. Collectively, our data demonstrate how a new molecular network on ATM regulates the cell cycle through the control of pRb phosphorylation. These findings support a new target of ATM.
Pizarro
Javier G
JG
Unitat de Farmacologia i Farmacognosia, Institut de Biomedicina (IBUB), Centro deInvestigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), Facultat de Farmacia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona E-08028, Spain.
Folch
Jaume
J
de la Torre
Aurelio Vazquez
AV
Junyent
Felix
F
Verdaguer
Ester
E
Jordan
Joaquin
J
Pallas
Merce
M
Camins
Antoni
A
D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009025:Morpholines; D011753:Pyrones; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010768:Phosphoserine; D006861:Hydrogen Peroxide; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases