Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53

Abstract

The p53 tumor suppressor protein is activated and phosphorylated on serine-15 in response to various DNA damaging agents. The gene product mutated in ataxia telangiectasia, ATM, acts upstream of p53 in a signal transduction pathway initiated by ionizing radiation. Immunoprecipitated ATM had intrinsic protein kinase activity and phosphorylated p53 on serine-15 in a manganese-dependent manner. Ionizing radiation, but not ultraviolet radiation, rapidly enhanced this p53-directed kinase activity of endogenous ATM. These observations, along with the fact that phosphorylation of p53 on serine-15 in response to ionizing radiation is reduced in ataxia telangiectasia cells, suggest that ATM is a protein kinase that phosphorylates p53 in vivo.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…The Cterminal half of the ATM gene contains sequence similarity to several DNA checkpoint genes and a domain homologous to phosphatidylinositol 3-kinase, consistent with the notion that the ATM protein functions as a protein kinase that phosphorylates p53 on Ser15 and thereby contributes to p53 activation (Banin et al, 1998;Canman et al, 1998). It is noteworthy that the phenotypic defects in AT are not merely the result of insu cient p53 induction after IR.…”

“…Several protein kinases can phosphorylate distinct domains of p53 in Structure and function of p53 protein P May and E May vitro. For example the DNA-PK (DNA-activated protein kinase), ATM kinase, (Banin et al, 1998;Canman et al, 1998) and CK1 (casein kinase I-like protein kinase), CDK-activating kinase (CAK) each phosphorylate di erent sites in the N-terminal transactivation domain of p53 (reviewed by Steegenga et al, 1996;Giaccia and Kastan, 1998;Chernov et al, 1998) (Figure 1). These phosphorylation events e ect the transactivation function of p53.…”

Interplay between ATM and ATR in the regulation of common fragile site stability

“…It is well established that ATM kinase activity is enhanced by DSBs (Banin et al, 1998;Canman et al, 1998), however, ATM was also shown to be phosphorylated in the absence of visible DSBs, for example, following replication arrest by thymidine (Bolderson et al, 2004). Previous studies have shown that following DSBs phosphorylated ATM forms nuclear foci, whereas following alterations in the chromatin structure without detectble DSBs, a diffused staining across the nucleus is observed (Bakkenist and Kastan, 2003).…”

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

“…Activated PIKKs phosphorylate various downstream targets involved in controlling cell cycle checkpoints, DNA repair and apoptotic pathways. These include p53, Chk1, Chk2, Brca-1, Rad9, Rad17, H2AX and others (Canman et al, 1998;Cortez et al, 1999;Bao et al, 2001;Chen et al, 2001;Bartek and Lukas, 2003;Stiff et al, 2004). Of particular importance to checkpoint activation is p53 phosphorylation on serine 15.…”

“…Of particular importance to checkpoint activation is p53 phosphorylation on serine 15. ATM can directly phosphorylate p53 (Ser15) in response to IR while ATR is critical in the same response to UV (Canman et al, 1998;Tibbetts et al, 1999). Additionally, p53 is phosphorylated on Ser20 by Chk1 or Chk2, which are targets for ATR and ATM signaling, respectively, although some cross-talk exists between the pathways (Bartek and Lukas, 2003).…”