The endogenous pacemaker located in the mammalian suprachiasmatic nucleus (SCN) maintains 24 hr periodicity over an array of biochemical, physiological and behavioral processes. The inherent timing mechanism of the SCN is entrained by external time cues, of which light is the most potent. Recent evidence has indicated the p42/44 mitogen activated protein kinase (MAPK) signaling pathway couples light to clock entrainment. As an initial characterization of how MAPK signaling affects the clock, I have compiled data indicating that members of the p90 ribosomal S6 kinase (RSK) and mitogen and stress activated kinase (MSK) families function as MAPK-regulated kinases in the SCN. Given the roles of these kinases in transcriptional regulation, I hypothesize that RSKs and MSKs couple light to gene expression and, in turn, entrainment of the mammalian circadian clock.
The specific aims of this proposal are to 1) determine the contribution of ERK and its downstream targets MSKs and RSKs to the expression of light-activated, circadian clock-regulated, genes, and 2) test the hypothesis that MSKs and RSKs couple light to entrainment of the circadian clock. A combination of cellular, molecular and behavioral assays will be used. ? ?
| Lee, Boyoung; Almad, Akshata; Butcher, Greg Q et al. (2007) Protein kinase C modulates the phase-delaying effects of light in the mammalian circadian clock. Eur J Neurosci 26:451-62 |
| Butcher, Greg Q; Lee, Boyoung; Cheng, Hai-Ying M et al. (2005) Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism. J Neurosci 25:5305-13 |
| Lee, Boyoung; Butcher, Greg Q; Hoyt, Kari R et al. (2005) Activity-dependent neuroprotection and cAMP response element-binding protein (CREB): kinase coupling, stimulus intensity, and temporal regulation of CREB phosphorylation at serine 133. J Neurosci 25:1137-48 |
