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Molecular events in radiation transformation.

R G Syljuåsen1, B Krolewski, J B Little

  • 1Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.

Radiation Research
|December 20, 2000
PubMed
Summary
This summary is machine-generated.

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Loss of cell cycle control and altered cell cycle proteins are early events in radiation-induced cancer, occurring independently of TP53 mutations. These changes are associated with malignant cell transformation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Alterations in cell cycle gene regulation and loss of radiation-induced G1 arrest are observed in human tumor cell lines.
  • It remains unclear if these changes are early or late events in tumor development or artifacts of cell culture.

Purpose of the Study:

  • To investigate whether alterations in cell cycle regulation and G1 arrest occur early in the process of oncogenic transformation.
  • To determine the role of TP53 mutations in radiation-induced transformation and loss of cell cycle control.

Main Methods:

  • Utilized a model system of normal and radiation-transformed C3H 10T(1/2) mouse fibroblast cell clones.
  • Compared transformed clones with parental wild-type cells.
  • Assessed TP53 mutations and expression, radiation-induced G1-phase arrest, and levels of cell cycle regulatory proteins (Cdkn1a, cyclin D1, cyclin E).

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Main Results:

  • TP53 mutations were found in approximately 25% of transformed clones, but appeared to be late events.
  • Loss of radiation-induced G1-phase arrest was observed in all transformed clones, irrespective of TP53 status.
  • Increased constitutive expression of Cdkn1a protein and elevated levels of cyclin D1 and cyclin E were noted in transformed clones.

Conclusions:

  • Loss of G1-phase checkpoint control, independent of TP53 status, is an early event in radiation-induced carcinogenesis.
  • Altered expression of cell cycle regulatory proteins is associated with malignant transformation.
  • These findings suggest that cell cycle dysregulation precedes or accompanies the initial stages of malignant transformation.