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CDC2 is down-regulated by ionizing radiation in a p53-dependent manner

E I Azzam1, S M de Toledo, M J Pykett

  • 1Laboratory of Radiobiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
|January 7, 1998
PubMed

Insights

Ionizing radiation exposure down-regulates CDC2 expression in mammalian cells. This process is dependent on the tumor suppressor p53 and involves the inhibitor p21Waf1, impacting cell cycle progression.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Radiation biology

Background:

  • Mammalian cells exhibit cell cycle delays and altered cyclin-dependent kinase activity following ionizing radiation exposure.
  • The CDC2 gene product is crucial for cell cycle progression, but regulatory signaling post-DNA damage remains unclear.

Purpose of the Study:

  • To investigate the signaling pathways regulating CDC2 expression after ionizing radiation exposure.
  • To determine the role of p53 and p21Waf1 in the cellular response to DNA damage.

Main Methods:

  • Irradiation of human and mouse fibroblasts with varying doses of ionizing radiation.
  • Analysis of cdc2 mRNA and protein levels.
  • Assessment of p53 and p21Waf1 protein induction.
  • Studies utilizing p53-nonfunctional human cells and p53-/- or p21-/- mouse embryo fibroblasts.

Main Results:

  • Ionizing radiation down-regulates cdc2 mRNA and protein in normal fibroblasts.
  • This down-regulation is preceded by the induction of p53 and p21Waf1.
  • CDC2 down-regulation is abrogated in cells lacking functional p53 or p21Waf1.
  • A correlation exists between delayed DNA synthesis initiation and reduced CDC2 expression in irradiated cells.

Conclusions:

  • CDC2 down-regulation following irradiation is a p53-dependent event.
  • The cyclin-dependent kinase inhibitor p21Waf1 acts as a negative regulator of CDC2 expression in response to DNA damage.
  • These findings elucidate a key mechanism in the mammalian cellular response to ionizing radiation and DNA damage.

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