Big Ben Rings in a Lesson on Biological Clocks

Abstract

There is a long history of experimental work seeking a connection between circadian clocks and the cell cycle. For some eukaryotic, unicellular systems, the evidence is quite good—photocycles that entrain circadian rhythms reset ∼24 hr rhythms of cell division that persist for many days in constant darkness or constant light (reviewed by Edmunds, 1988xEdmunds, L.N. Jr. See all ReferencesEdmunds, 1988). Are there comparable interactions in multicellular organisms, even mammals?Cheng Chi Lee produced a list of novel phenotypes in Per 2 mutant mice that indicate action of PER as a tumor suppressor, as a regulator of cell growth, and as a component of the DNA damage response (Fu et al., 2002xThe circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Fu, L., Pelicano, H., Liu, J., Huang, P., and Lee, C. Cell. 2002; 111: 41–50Abstract | Full Text | Full Text PDF | PubMed | Scopus (690)See all References(Fu et al., 2002). First, there is a highly significant difference in the frequency of spontaneous and γ irradiation-induced tumors and hyperplasia in Per2 mice. In fact, all Per2 mice develop an otherwise rarely encountered, salivary gland hyperplasia by the age of 8 months. Per2 mice were also found to be unusually resistant to irradiation-induced apoptosis. This deficiency appears to be linked to reduced induction of p53 and associated cytochrome c regulation. Even more surprising, Lee's laboratory reports that genes composing the clock are induced by γ irradiation in wild-type but not Per2 mice, suggesting a possible role for the clock itself in the apoptotic response.Timed expression of several genes central to cell cycle control is altered in Per2 mice. For example, both cyclin A and cyclin D1 mRNAs accumulate in hepatocytes from wild-type mice with a circadian rhythm. The phase and amplitude of both rhythms appear to be substantially altered in Per2 mice (Fu et al., 2002xThe circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Fu, L., Pelicano, H., Liu, J., Huang, P., and Lee, C. Cell. 2002; 111: 41–50Abstract | Full Text | Full Text PDF | PubMed | Scopus (690)See all References(Fu et al., 2002). Since cyclin D1 is a target for c-myc, the latter gene's regulation was also examined; c-myc too oscillates with a circadian rhythm that is significantly altered in Per2 mutants. Lee suggested that, in particular, strong upward swings in c-myc expression may underlie the salivary gland hyperplasia his laboratory sees in Per2 mice.Testing a focused proposal of this sort will be challenging because circadian clocks command such broad programs of timed gene expression. Recall that in the mouse, 24 hr clocks not only determine the sequential expression of hundreds of genes, but the list of clock-controlled targets is tissue specific, amplifying the complexity of the temporal code. Presumably, a Per2 mutant response ripples through the entire program of rhythmic expression in each tissue. Surely connections between individual clock-controlled genes and elements of the Per2 phenotype will remain speculative for awhile. These difficulties aside, the mouse Per2 study does remind us that a dominant mutation of this gene has been associated with FASPS, a familial sleep disorder in humans (Toh et al., 2001xAn hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Toh, K.L., Jones, C.R., He, Y., Eide, E.J., Hinz, W.A., Virshup, D.M., Ptacek, L.J., and Fu, Y.H. Science. 2001; 291: 1040–1043Crossref | PubMed | Scopus (824)See all References(Toh et al., 2001). It would be fascinating to study the range of phenotypic effects associated with this Per2 mutation in transgenic mice.