Ultraviolet light induces the sustained unscheduled expression of cyclin E in the absence of functional p53.
Cell cycle progression is regulated through changes in the activity of cyclin-dependent kinases that are, in turn, regulated by the expression of their respective cyclin partners. In primary cells, cyclin E expression increases through the G(1) phase of the cell cycle and peaks near the G(1)/S boundary. The unscheduled expression of cyclin E in primary human fibroblasts leads to chromosomal instability that is greatly increased by loss of the p53 tumour suppressor. Intriguingly, ultraviolet light (UV), the most prevalent environmental carcinogen, is similarly known to induce chromosomal instability more dramatically in the absence of p53. Here we report that UV light transiently increased the expression of cyclin E in normal human fibroblasts. Strikingly, cyclin E levels remained elevated for an extended period of time in the absence of functional p53. UV-induced cyclin E expression was not restricted to the G(1)/S boundary but remained elevated throughout S phase and this correlated with a massive accumulation of p53-deficient fibroblasts in this phase of the cell cycle. Forced expression of cyclin E alone was insufficient to cause a similar S phase arrest but forced expression of cyclin E led to an increase in the proportion of UV-irradiated cells in S phase. The present work suggests that p53 affects S phase progression following UV exposure by preventing the sustained unscheduled expression of cyclin E and that this may limit the clastogenic and carcinogenic effects of UV light.
Stubbert
Lawton J
LJ
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, CA.
Spronck
Jennifer C
JC
Hamill
Jeff D
JD
McKay
Bruce C
BC
D002453:Cell Cycle; D002478:Cells, Cultured; D019927:Cyclin E / Q000096:biosynthesis / Q000528:radiation effects*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000528:radiation effects
D019927:Cyclin E; D016159:Tumor Suppressor Protein p53