Home LiteratureArticle Details
PMID: 10082548 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA double-strand breaks.

Molecular and cellular biology ·Vol. 19 ·No. 4 ·1999-04-00 ·Pages 2828-34

Nakagawa K, Taya Y, Tamai K, Yamaizumi M

Abstract

Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.

MeSH Terms
Acetylcysteine/analogs & derivatives,pharmacology Ataxia Telangiectasia/metabolism Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins Cysteine Endopeptidases/metabolism Cysteine Proteinase Inhibitors/pharmacology DNA Damage/physiology DNA-Binding Proteins Deoxyribonucleases, Type II Site-Specific/metabolism Heat-Shock Response Humans Multienzyme Complexes/metabolism Phosphorylation Proteasome Endopeptidase Complex Protein Serine-Threonine Kinases Proteins/metabolism Serine/metabolism Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins Xeroderma Pigmentosum/metabolism
Chemicals
Cell Cycle Proteins Cysteine Proteinase Inhibitors DNA-Binding Proteins Multienzyme Complexes Proteins Tumor Suppressor Protein p53 Tumor Suppressor Proteins lactacystin Serine ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Deoxyribonucleases, Type II Site-Specific GGCC-specific type II deoxyribonucleases Cysteine Endopeptidases Proteasome Endopeptidase Complex Acetylcysteine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Nakagawa K
Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto 862-0976, Japan.
Taya Y
Tamai K
Yamaizumi M
References (33)
33 references, click to expand
  1. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.
    Mol Cell Biol. 1994 Mar;14(3):1815-23 PMID: 8114714
  2. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells.
    Oncogene. 1993 Dec;8(12):3307-12 PMID: 8247533
  3. Expression of wild-type p53 during the cell cycle in normal human mammary epithelial cells.
    Cell Growth Differ. 1994 Mar;5(3):295-304 PMID: 8018562
  4. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status.
    Mol Cell Biol. 1994 Sep;14(9):6264-77 PMID: 8065358
  5. U.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle.
    Oncogene. 1994 Oct;9(10):2775-84 PMID: 8084582
  6. The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.
    Cancer Res. 1994 Oct 1;54(19):5054-8 PMID: 7923116
  7. UVs syndrome, a new general category of photosensitive disorder with defective DNA repair, is distinct from xeroderma pigmentosum variant and rodent complementation group I.
    Am J Hum Genet. 1995 Jun;56(6):1267-76 PMID: 7539208
  8. Nuclear accumulation of p53 in normal human fibroblasts is induced by various cellular stresses which evoke the heat shock response, independently of the cell cycle.
    Jpn J Cancer Res. 1995 May;86(5):415-8 PMID: 7790313
  9. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species.
    Hum Mol Genet. 1995 Nov;4(11):2025-32 PMID: 8589678
  10. p53: puzzle and paradigm.
    Genes Dev. 1996 May 1;10(9):1054-72 PMID: 8654922
  11. Microinjection of partially purified protein factor restores DNA damage specifically in group A of xeroderma pigmentosum cells.
    Proc Natl Acad Sci U S A. 1986 Mar;83(5):1476-9 PMID: 3456596
  12. Determination of the chromosomal site for the human radiosensitive ataxia telangiectasia gene by chromosome transfer.
    Mutat Res. 1991 Sep-Oct;250(1-2):337-43 PMID: 1944350
  13. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.
    Nature. 1992 Mar 19;356(6366):215-21 PMID: 1552940
  14. Induction of chromosomal damage by restriction endonuclease in CHO cells porated with streptolysin O.
    Mutat Res. 1992 Jul;268(1):27-34 PMID: 1378183
  15. Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53.
    Mol Cell Biol. 1992 Nov;12(11):5041-9 PMID: 1406679
  16. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia.
    Cell. 1992 Nov 13;71(4):587-97 PMID: 1423616
  17. Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents.
    Oncogene. 1993 Feb;8(2):307-18 PMID: 8426740
  18. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53.
    Nature. 1993 Apr 29;362(6423):857-60 PMID: 8479525
  19. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes?
    Cell. 1993 Nov 19;75(4):765-78 PMID: 8242748
  20. In vivo ubiquitination and proteasome-mediated degradation of p53(1).
    Cancer Res. 1996 Jun 1;56(11):2649-54 PMID: 8653711
  21. DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage.
    Cancer Res. 1997 Jan 1;57(1):68-74 PMID: 8988043
  22. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2.
    EMBO J. 1996 Dec 16;15(24):7060-9 PMID: 9003781
  23. Regulation of p53 stability by Mdm2.
    Nature. 1997 May 15;387(6630):299-303 PMID: 9153396
  24. Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation.
    Mol Cell Biol. 1997 Sep;17(9):5016-22 PMID: 9271379
  25. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2.
    Cell. 1997 Oct 31;91(3):325-34 PMID: 9363941
  26. DNA damage induces phosphorylation of the amino terminus of p53.
    Genes Dev. 1997 Dec 15;11(24):3471-81 PMID: 9407038
  27. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.
    FEBS Lett. 1997 Dec 22;420(1):25-7 PMID: 9450543
  28. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.
    Cell. 1998 May 1;93(3):477-86 PMID: 9590181
  29. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins.
    Nat Genet. 1998 Jun;19(2):175-8 PMID: 9620776
  30. Mec1p is essential for phosphorylation of the yeast DNA damage checkpoint protein Ddc1p, which physically interacts with Mec3p.
    EMBO J. 1998 Jul 15;17(14):4199-209 PMID: 9670034
  31. Enhanced phosphorylation of p53 by ATM in response to DNA damage.
    Science. 1998 Sep 11;281(5383):1674-7 PMID: 9733514
  32. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
    Science. 1998 Sep 11;281(5383):1677-9 PMID: 9733515
  33. Terminal differentiation and apoptosis in experimental lung metastases of human osteogenic sarcoma cells by wild type p53.
    Oncogene. 1994 Jul;9(7):1877-83 PMID: 8208533
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.4.2828
Published
1999-04-00
Pages
2828-34
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC84075
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.19.4.2828 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2