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ATM is required for rapid degradation of cyclin D1 in response to gamma-irradiation

Dong Wan Choo1, Hye Jung Baek, Noboru Motoyama

  • 1Radiation Medicine Branch, National Cancer Center, Goyang-si, Gyeonggi-do, South Korea.

Biochemical and Biophysical Research Communications
|December 17, 2008
PubMed

Insights

Gamma-irradiation rapidly degrades cyclin D1 via a p53-independent pathway involving ubiquitination and proteasomes. ATM, not GSK-3beta, mediates this degradation, crucial for cell-cycle arrest and genomic integrity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • DNA damage triggers cell-cycle arrest for repair, preventing replication.
  • Cyclin D1 is critical for G1/S phase transition and implicated in cancer development.
  • Understanding cyclin D1 regulation post-DNA damage is vital for cancer prevention.

Purpose of the Study:

  • To investigate the proteolytic regulation of cyclin D1 expression following gamma-irradiation.
  • To elucidate the role of p53, ubiquitination, proteasomes, GSK-3beta, and ATM in cyclin D1 degradation.

Main Methods:

  • Analysis of cyclin D1 protein levels after gamma-irradiation.
  • Assessment of cyclin D1 ubiquitination and degradation in the presence of proteasome inhibitors.
  • Study of cyclin D1 mutant protein stability (T286A) and effects of GSK-3beta and ATM inhibitors.

Main Results:

  • Gamma-irradiation caused rapid, p53-independent cyclin D1 reduction.
  • Cyclin D1 degradation was mediated by ubiquitination and proteasomal pathways.
  • ATM inhibition, but not GSK-3beta inhibition, prevented irradiation-induced cyclin D1 degradation.
  • Mutation of Thr286 rendered cyclin D1 resistant to irradiation-induced proteolysis.

Conclusions:

  • ATM-mediated regulation of cyclin D1 stability is essential for cell-cycle arrest and genomic integrity.
  • Disruption of the ATM-cyclin D1 crosstalk may enhance cancer susceptibility.

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