Regulation by ionizing radiation of CDC2, cyclin A, cyclin B, Thymidine Kinace, Topoisomerase IIα, and RAD51 expression in normal human diploid fibroblasts is dependent on p53/p21(Waf1)

Sonia M. De Toledo, Edouard I. Azzam, Peter Keng, Shelley Laffrenier, John B. Little

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Abstract

Induced cell cycle delays were among the first described cellular responses to ionizing radiation (IR). To understand the sensitivity and the molecular events involved in the response to low doses of IR and to examine the role of p53 and its downstream effector p21(Waf1), we measured changes in expression of genes postulated to be involved in the cellular response to IR. Expression levels were examined in normal human diploid fibroblasts irradiated and maintained in quiescent density-inhibited growth up to 24-48 h after exposure to X-ray doses as low as 0.1-0.3 Gy, which have negligible effects on cell survival. Among 31 genes analyzed, we observed down- regulation in response to IR of the mRNA levels of CDC2, cyclin A, cyclin B, thymidine kinase, topoisomerase IIα, and RAD51. A similar reduction in the expression levels of these genes occurred when irradiated cells were released from confluence and allowed to proliferate. This was not observed in cells in which p53 function was defective and up-regulation of p21(Waf1) levels either did not occur (E6 transfected normal human fibroblasts and Li-Fraumeni fibroblasts) or was delayed (ataxia telangiectasia fibroblasts) after irradiation. Down-regulation was also absent in p21(Waf1)-null mouse embryo fibroblasts (MEFs) but occurred at a lower level in p53-null MEFs, due to slight increases in p21(Waf1) levels by a p53-independent pathway. These findings indicate that the down-regulation of these cell cycle regulated genes in irradiated cells is p53-dependent and involves its effector p21(Waf1). Although no down-regulation in the expression of genes involved in G2-M was observed in p53 or in p21(Waf1)-null MEFs, these cells showed a G2-M delay after irradiation, indicating that the expression levels of these genes does not regulate the G2-M delay.

Original languageEnglish (US)
Pages (from-to)887-896
Number of pages10
JournalCell Growth and Differentiation
Volume9
Issue number11
StatePublished - Nov 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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