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

Publication ,  Journal Article
Maya, R; Balass, M; Kim, ST; Shkedy, D; Leal, JF; Shifman, O; Moas, M; Buschmann, T; Ronai, Z; Shiloh, Y; Kastan, MB; Katzir, E; Oren, M
Published in: Genes Dev
May 1, 2001

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.

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Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

May 1, 2001

Volume

15

Issue

9

Start / End Page

1067 / 1077

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Serine
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Nuclear Proteins
  • Mutation
  • Microinjections
 

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Maya, R., Balass, M., Kim, S. T., Shkedy, D., Leal, J. F., Shifman, O., … Oren, M. (2001). ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev, 15(9), 1067–1077. https://doi.org/10.1101/gad.886901
Maya, R., M. Balass, S. T. Kim, D. Shkedy, J. F. Leal, O. Shifman, M. Moas, et al. “ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage.Genes Dev 15, no. 9 (May 1, 2001): 1067–77. https://doi.org/10.1101/gad.886901.
Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 2001 May 1;15(9):1067–77.
Maya, R., et al. “ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage.Genes Dev, vol. 15, no. 9, May 2001, pp. 1067–77. Pubmed, doi:10.1101/gad.886901.
Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, Moas M, Buschmann T, Ronai Z, Shiloh Y, Kastan MB, Katzir E, Oren M. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 2001 May 1;15(9):1067–1077.

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

May 1, 2001

Volume

15

Issue

9

Start / End Page

1067 / 1077

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Serine
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Nuclear Proteins
  • Mutation
  • Microinjections