ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation.
The p53 tumor suppressor protein preserves genome integrity by regulating growth arrest and apoptosis in response to DNA damage. In response to ionizing radiation (IR), ATM, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of Ser(15) and (indirectly) Ser(20). Here we show that phosphorylation of p53 on Ser(46), a residue important for p53 apoptotic activity, as well as on Ser(9), in response to IR also is dependent on the ATM protein kinase. IR-induced phosphorylation at Ser(46) was inhibited by wortmannin, a phosphatidylinositol 3-kinase inhibitor, but not PD169316, a p38 MAPK inhibitor. p53 C-terminal acetylation at Lys(320) and Lys(382), which may stabilize p53 and activate sequence-specific DNA binding, required Ser(15) phosphorylation by ATM and was enhanced by phosphorylation at nearby residues including Ser(6), Ser(9), and Thr(18). These observations, together with the proposed role of Ser(46) phosphorylation in mediating apoptosis, suggest that ATM is involved in the initiation of p53-dependent apoptosis after IR in human lymphoblastoid cells.
Saito
Shin'ichi
S
Biology Department, Brookhaven National Laboratory, 50 Bell Avenue, Upton, New York 11973, USA.
Goodarzi
Aaron A
AA
Higashimoto
Yuichiro
Y
Noda
Yuka
Y
Lees-Miller
Susan P
SP
Appella
Ettore
E
Anderson
Carl W
CW
D000107:Acetylation; D000730:Androstadienes / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011839:Radiation, Ionizing; D012694:Serine / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism / Q000528:radiation effects*; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin
D000730:Androstadienes; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; D000077191:Wortmannin