Science

Circadian clock controls cell cycling

Last Updated: 2003-08-21 17:39:40 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Intracellular circadian clock genes partially regulate the timing and efficiency of cell cycle events, Japanese scientists report. Elucidating the mechanisms of these events may help to refine strategies for treating cancer, they suggest in the August 21st online edition of Science.

Dr. Hitoshi Okamura of Kobe University Graduate School of Medicine and colleagues used partially hepatectomized mice to investigate molecular mechanisms responsible for the diurnal regulation of mitosis in rapidly regenerating tissue. Depending on the timing of the hepatectomy, in vivo hepatocytes differed in the timing of their entry into M phase.

When they analyzed expression profiles of 68 cell cycle-related genes, they observed three that showed "remarkably different" profiles depending on the time at which hepatectomy was conducted: cyclin B1, Cdc2, and wee1. This suggests that "the transcript level regulation of [these three genes] contributes to the timing of entry into mitosis," they write.

The research team also demonstrated that the wee1 gene, the product of which controls the timing of M phase entry, is under circadian regulation at the mRNA, protein and kinase activity levels.

Dr. Okamura's group repeated their studies in mice that lacked the clock regulator cryptochromes (Cry), which "completely lack free-running rhythmicity." At 72 hours after hepatectomy, the weight of regenerating liver in the Cry-deficient mice was significantly lower than that of wild-type mice. They found that S-phase kinetics did not differ, but progression to M-phase was impaired, leading to a very low level of mitotic cells.

The authors traced this impairment to markedly deregulated expression of many cell-cycle-related genes, including cyclin B, cdc2, and wee1. These findings indicate that "the circadian clock-wee1 pathway functions as a vital means of controlling the cell cycle in vivo."

Finally, Dr. Okamura and associates employed immunohistochemical staining to demonstrate that the circadian clock oscillates accurately at the level of single proliferating cells. They theorize that similar events operate in continuously proliferating tissues, such as gastric mucosa and bone marrow, and that these mechanisms underlie observed variations in the toxicity and antitumor effects of some chemotherapy drugs.

Science, August 21, 2003 online edition.