ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage.

By R. Maya, M. Balass, Seong Tae Kim, D. Shkedy, J. Leal, O. Shifman, Miri Moas, T. Buschmann, Z. Ronai, Yosef Shiloh and 3 more. Genes & Development, 2001

796 citations recorded by the source corpus.

The p53 tumor suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. The rapid activation of p53 by ionizing radiation and radiomimetic agents is largely dependent on the ATM kinase. p53 is phosphorylated by ATM shortly after DNA damage, resulting in enhanced stability and activity of p53. The Mdm2 oncoprotein is a pivotal negative regulator of p53. In response to ionizing radiation and radiomimetic drugs, Mdm2 undergoes rapid ATM-dependent phosphorylation prior to p53 accumulation. This results in a decrease in its reactivity with the 2A10 monoclonal antibody. Phage display analysis identified a consensus 2A10 recognition sequence, possessing the core motif DYS. Unexpectedly, this motif appears twice within the human Mdm2 molecule, at positions corresponding to residues 258-260 and 393-395. Both putative 2A10 epitopes are highly conserved and encompass potential phosphorylation sites. Serine 395, residing within the carboxy-terminal 2A10 epitope, is the major target on Mdm2 for phosphorylation by ATM in vitro. Mutational analysis supports the conclusion that Mdm2 undergoes ATM-dependent phosphorylation on serine 395 in vivo in response to DNA damage. The data further suggests that phosphorylated Mdm2 may be less capable of promoting the nucleo-cytoplasmic shuttling of p53 and its subsequent degradation, thereby enabling p53 accumulation. Our findings imply that activation of p53 by DNA damage is achieved, in part, through attenuation of the p53-inhibitory potential of Mdm2.

Subfields: Biotechnology, Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/19c6e5c7de18744509032f69ee8dda92f504353d

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In Biotechnology

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In Oncology

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Citations in the corpus

• The complexity of p53 stabilization and activation (2006, background): “The phosphorylated form of MDM2 appears to be less capable of nucleo-cytoplasmic shuttling of p53, suggesting that the MDM2 phosphorylation destabilizes the interaction with p53.(57) ATM also plays a key role in phosphorylating p53 on Ser 15 and other sites in response to DNA double-strand”
• Regulation of HDM2 activity by the ribosomal protein L11. (2003, neutral): “CANCER CELL : JUNE 2003 · VOL. 3 · COPYRIGHT 2003 CELL PRESS 577 al., 2001; Chehab et al., 2000; Goldberg et al., 2002; Hirao et al., 2000; Maya et al., 2001; Shieh et al., 2000).”
• USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010, neutral): “Furthermore, ATM-dependent phosphorylation of Mdm2 and Mdmx could destabilize these proteins and compromise their activity (Khosravi et al., 1999; Maya et al., 2001; Meulmeester et al., 2005; Pereg et al., 2005; Stommel and Wahl, 2004).”
• p53 ubiquitination: Mdm2 and beyond. (2006, background): “In addition, modifications occurring on Mdm2 can also disrupt their direct interaction during specific DNA damage events, such as ionizing radiation, when Mdm2 is phosphorylated at serine 395 (Maya et al., 2001).”
• Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM (2004, background): “The role of the ATM protein in the stabilization of p53 in response to DNA double-strand break-inducing agents is very well established (4, 10, 11, 13, 44).”
• The MDM2-p53 interaction. (2003, background): “largely impairs the ability of MDM2 to promote p53 degradation (74).”
• Hydrogen peroxide sensing, signaling and regulation of transcription factors (2014, background): “The H2O2activated kinases Ataxia telangiectasia mutated (ATM) [196] and c-ABL [197] phosphorylate MDM2 leading to the fast activation of TP53 [198][199].”
• DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation (2003, background): “These include p53, Mdm2 and Chk2 in the G1 checkpoin”