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ATM activation in normal human tissues and testicular cancer.

Publication ,  Journal Article
Bartkova, J; Bakkenist, CJ; Rajpert-De Meyts, E; Skakkebaek, NE; Sehested, M; Lukas, J; Kastan, MB; Bartek, J
Published in: Cell Cycle
June 2005

The ATM kinase is a tumor suppressor and key regulator of biological responses to DNA damage. Cultured cells respond to genotoxic insults that induce DNA double-strand breaks by prompt activation of ATM through its autophosphorylation on serine 1981. However, whether ATM-S1981 becomes phosphorylated in vivo, for example during physiological processes that generate DSBs, is unknown. Here we produced phospho-specific monoclonal antibodies against S1981-phosphorylated ATM (pS-ATM), and applied them to immunohistochemical analyses of a wide range of normal human tissues and testicular tumors. Our data show that regardless of proliferation and differentiation, most human tissues contain only the S1981-nonphosphorylated, inactive form of ATM. In contrast, nuclear staining for pS-ATM was detected in subsets of bone-marrow lymphocytes and primary spermatocytes in the adult testes, cell types in which DSBs are generated during physiological V(D)J recombination and meiotic recombination, respectively. Among testicular germ-cell tumors, an aberrant constitutive pS-ATM was observed especially in embryonal carcinomas, less in seminomas, and only modestly in teratomas and the pre-invasive carcinoma-in-situ stage. Compared with pS-ATM, phosphorylated histone H2AX (gammaH2AX), another DNA damage marker and ATM substrate, was detected in a higher proportion of cancer cells, and also in normal fetal gonocytes, and a wider range of adult spermatocyte differentiation stages. Collectively, our results strongly support the physiological relevance of the recently proposed model of ATM autoactivation, and provide further evidence for constitutive activation of the DNA damage machinery during cancer development. The new tools characterized here should facilitate monitoring of ATM activation in clinical specimens, and help develop future treatment strategies.

Duke Scholars

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Published In

Cell Cycle

DOI

EISSN

1551-4005

Publication Date

June 2005

Volume

4

Issue

6

Start / End Page

838 / 845

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Testicular Neoplasms
  • Stomach
  • Recombinant Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Organ Specificity
  • Neoplasms, Germ Cell and Embryonal
  • Mutation
  • Male
 

Citation

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Bartkova, J., Bakkenist, C. J., Rajpert-De Meyts, E., Skakkebaek, N. E., Sehested, M., Lukas, J., … Bartek, J. (2005). ATM activation in normal human tissues and testicular cancer. Cell Cycle, 4(6), 838–845. https://doi.org/10.4161/cc.4.6.1742
Bartkova, Jirina, Christopher J. Bakkenist, Ewa Rajpert-De Meyts, Niels E. Skakkebaek, Maxwell Sehested, Jiri Lukas, Michael B. Kastan, and Jiri Bartek. “ATM activation in normal human tissues and testicular cancer.Cell Cycle 4, no. 6 (June 2005): 838–45. https://doi.org/10.4161/cc.4.6.1742.
Bartkova J, Bakkenist CJ, Rajpert-De Meyts E, Skakkebaek NE, Sehested M, Lukas J, et al. ATM activation in normal human tissues and testicular cancer. Cell Cycle. 2005 Jun;4(6):838–45.
Bartkova, Jirina, et al. “ATM activation in normal human tissues and testicular cancer.Cell Cycle, vol. 4, no. 6, June 2005, pp. 838–45. Pubmed, doi:10.4161/cc.4.6.1742.
Bartkova J, Bakkenist CJ, Rajpert-De Meyts E, Skakkebaek NE, Sehested M, Lukas J, Kastan MB, Bartek J. ATM activation in normal human tissues and testicular cancer. Cell Cycle. 2005 Jun;4(6):838–845.

Published In

Cell Cycle

DOI

EISSN

1551-4005

Publication Date

June 2005

Volume

4

Issue

6

Start / End Page

838 / 845

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Testicular Neoplasms
  • Stomach
  • Recombinant Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Organ Specificity
  • Neoplasms, Germ Cell and Embryonal
  • Mutation
  • Male