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J. Biol. Chem., Vol. 279, Issue 21, 22738-22746, May 21, 2004

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Regulation of the Circadian Oscillator in Xenopus Retinal Photoreceptors by Protein Kinases Sensitive to the Stress-activated Protein Kinase Inhibitor, SB 203580^*

Minoru Hasegawa and Gregory M. Cahill

From the Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001

Circadian rhythms are generated by transcriptional and translational feedback loops. Stress-activated protein kinases (SAPKs) are known to regulate transcription factors in response to a variety of extracellular stimuli. In the present study, we examined whether the SAPKs play a role in the circadian system in cultured Xenopus retinal photoreceptor layers. A 6-h pulse of SB 203580, an inhibitor of SAPKs, reset the circadian rhythm of melatonin in a phase-dependent manner similar to dark pulses. This phase-shifting effect was dose-dependent over the range of 1-100 µM. Treatment with SB 203580 also affected light-induced phase shifts, and light had no effect on the circadian oscillator in the presence of 100 µM SB 203580. In-gel kinase assays showed that SB 203580 selectively inhibited a small group of protein kinases in the photoreceptor cells. These SB 203580-sensitive kinases correspond to two isoforms of phosphorylated p38 MAPK and three isoforms of c-Jun N-terminal kinase (JNK). Further in vitro study demonstrated that SB 203580 also inhibited casein kinase I (CKI), which has been shown to regulate circadian rhythms in several organisms. However, a pharmacological inhibition of CKI reset the circadian oscillator in a phase-dependent manner distinct from that of SB 203580. This argues against a primary role of CKI in the phase-shifting effects of SB 203580. These results suggest that SB 203580 affects the circadian system by inhibiting p38 MAPKs or JNKs and that these protein kinases are candidate cellular signals in the regulation of the circadian oscillator in the Xenopus retinal photoreceptors.

Received for publication, February 8, 2004 , and in revised form, March 11, 2004.

^* This research was supported by National Institutes of Health Grant R01-MH49757 (to G. M. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001. Tel.: 713-743-2696; Fax: 713-743-2636; E-mail: hasegawa{at}uh.edu.

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