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In mammals, the circadian and stress systems (both centers of which are located in the hypothalamus) are involved in adaptation to predictable and unpredictable environmental stimuli, respectively. Although the interaction and relationship between these two systems are intriguing and have been studied in different ways since the “pre-clock gene” era, the molecular interaction between them remains largely unknown. Here, we show by systematic molecular biological analysis that acute physical stress elevated only Period1 (Per1) mRNA expression in mouse peripheral organs. Although behavioral rhythms in vivo and peripheral molecular clocks are rather stable against acute restraint stress, the results of a series of promoter analyses, including chromatin immunoprecipitation assays, indicate that a glucocorticoid-responsive element in the Per1 promoter is indispensable for induction of this mRNA both in vitro and in vivo. These results suggest that Per1 can be a potential stress marker and that a third pathway of Per1 transcriptional control may exist in addition to the clock-regulated CLOCK-BMAL1/E-box and light-responsive cAMP-responsive element-binding protein/cAMP-responsive element pathways. In mammals, the circadian and stress systems (both centers of which are located in the hypothalamus) are involved in adaptation to predictable and unpredictable environmental stimuli, respectively. Although the interaction and relationship between these two systems are intriguing and have been studied in different ways since the “pre-clock gene” era, the molecular interaction between them remains largely unknown. Here, we show by systematic molecular biological analysis that acute physical stress elevated only Period1 (Per1) mRNA expression in mouse peripheral organs. Although behavioral rhythms in vivo and peripheral molecular clocks are rather stable against acute restraint stress, the results of a series of promoter analyses, including chromatin immunoprecipitation assays, indicate that a glucocorticoid-responsive element in the Per1 promoter is indispensable for induction of this mRNA both in vitro and in vivo. These results suggest that Per1 can be a potential stress marker and that a third pathway of Per1 transcriptional control may exist in addition to the clock-regulated CLOCK-BMAL1/E-box and light-responsive cAMP-responsive element-binding protein/cAMP-responsive element pathways. The hypothalamus in mammals plays an essential role in maintaining homeostasis and has various functions, including hormonal secretion, regulation of vital phenomena, and circadian rhythms. Two systems deeply associated with the hypothalamus, the circadian and stress systems, are necessary for animals to adapt to their environment. The circadian system is responsible for adaptation to predictable aspects of the environment, whereas the stress systems are engaged for adaptation to its unpredictable aspects (1Meerlo P. Sgoifo A. Turek F.W. Stress. 2002; 5: 15-22Crossref PubMed Scopus (91) Google Scholar). The circadian system, which governs daily rhythms with periodicities ∼24 h in length, is generally viewed as consisting of three components, i.e. input, oscillator, and output. The input or entrainment signal is most often light, but it can also be other environmental cues, such as temperature, feeding, and social cues. In mammals, the light signals acting on the ganglion cells of the retina are conveyed through the retinohypothalamic tract to the suprachiasmatic nuclei (SCN) 3The abbreviations used are: SCNsuprachiasmatic nucleiCREcAMP-responsive elementCREBcAMP-responsive element-binding proteinLD12-h light/12-h darkRTreverse transcriptionmmouseGREglucocorticoid-responsive elementdGREdistal glucocorticoid-responsive elementpGREproximal glucocorticoid-responsive elementChIPchromatin immunoprecipitationGRglucocorticoid receptorCTcircadian timeZTZeitgeber time. in the anteroventral hypothalamus, which is a major circadian center. As the output, anatomically the SCN projects to at least four different neuronal targets: endocrine neurons, autonomic neurons of the paraventricular nucleus of the hypothalamus, other hypothalamic structures that transmit the circadian signal to other brain regions, and areas outside the hypothalamus (2Buijs R.M. Kalsbeek A. Nat. Rev. Neurosci. 2001; 2: 521-526Crossref PubMed Scopus (470) Google Scholar). Physiologically the clock's output drives various phenomena, such as locomotor activity, sleep-wake cycles, and hormonal secretion. Recent competitive and rapidly progressing research has revealed that molecular clocks “tick” not only in the central SCN, but also in peripheral tissues and even in immortalized cells (3Balsalobre A. Damiola F. Schibler U. Cell. 1998; 93: 929-937Abstract Full Text Full Text PDF PubMed Scopus (1572) Google Scholar, 4Schibler U. Sassone-Corsi P. Cell. 2002; 111: 919-922Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar, 5Hastings M.H. Reddy A.B. Maywood E.S. Nat. Rev. Neurosci. 2003; 4: 649-661Crossref PubMed Scopus (963) Google Scholar, 6Akashi M. Nishida E. 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Akashi M. Mamine T. Takumi T. BMC Mol. Biol. 2004; 5: 18Crossref PubMed Scopus (259) Google Scholar). The transcription of Per1 is activated by binding of the CLOCK-BMAL1 heterocomplex, both components of which are bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) proteins, to the E-boxes in the Per1 promoter (20Gekakis N. Staknis D. Nguyen H.B. Davis F.C. Wilsbacher L.D. King D.P. Takahashi J.S. Weitz C.J. Science. 1998; 280: 1564-1569Crossref PubMed Scopus (1566) Google Scholar). The translated PER1 is post-translationally modified by CK1δ or CK1ϵ (21Vielhaber E. Eide E. Rivers A. Gao Z.H. Virshup D.M. Mol. Cell. Biol. 2000; 20: 4888-4899Crossref PubMed Scopus (246) Google Scholar, 22Takano A. Shimizu K. Kani S. Buijs R.M. Okada M. Nagai K. FEBS Lett. 2000; 477: 106-112Crossref PubMed Scopus (67) Google Scholar) and, together with other clock such as is the nucleus to its K. M.J. S. Shearman L.P. Weaver D.R. Maywood E.S. M.H. Reppert S.M. 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However, with with such as and the molecular mechanisms of this and intriguing relationship between the circadian and stress systems have stress the circadian in circadian rhythms in or stress or clock is the In this we the expression of of clock and genes in mouse peripheral tissues as as their behavioral rhythms an acute restraint molecular and behavioral were 12-h light/12-h dark as a of the dark of the and were in the third or animals in this were by the were for h in a and in or and peripheral tissues and were The peripheral tissues were at in and was an system was with an entrainment the on to were in with an locomotor and as M. Takumi T. Nat. Mol. Biol. 12: PubMed Scopus Google Scholar). we used a J. Biol. 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Albrecht U. Zhuchenko O. Bailey J. Eichele G. Lee C.C. Cell. 1997; 90: 1003-1011Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar, 14Tei H. Okamura H. Shigeyoshi Y. Fukuhara C. Ozawa R. Hirose M. Sakaki Y. Nature. 1997; 389: 512-516Crossref PubMed Scopus (681) Google Scholar, 19Yamamoto T. Nakahata Y. Soma H. Akashi M. Mamine T. Takumi T. BMC Mol. Biol. 2004; 5: 18Crossref PubMed Scopus (259) Google Scholar). The most of circadian as a is that a of clock transcription to the to Per1 transcription (20Gekakis N. Staknis D. Nguyen H.B. Davis F.C. Wilsbacher L.D. King D.P. Takahashi J.S. Weitz C.J. Science. 1998; 280: 1564-1569Crossref PubMed Scopus (1566) Google Scholar). at the and not in the SCN (15Takumi T. Taguchi K. Miyake S. Sakakida Y. Takashima N. Matsubara C. Maebayashi Y. Okumura K. Takekida S. Yamamoto S. Yagita K. Yan L. Young M.W. Okamura H. EMBO J. 1998; 17: 4753-4759Crossref PubMed Scopus (219) Google Scholar, 16Takumi T. Matsubara C. Shigeyoshi Y. Taguchi K. Yagita K. Maebayashi Y. Sakakida Y. Okumura K. Takashima N. Okamura H. Genes Cells. 1998; 3: 167-176Crossref PubMed Scopus (193) Google and the induction of mRNA is for or M. Y. Takahashi S. H. T. M. S. H. Sakaki Y. S. J. Neurosci. 1999; PubMed Google Scholar). The and not the that and as a of for the regulation of genes by light N. Reppert S.M. Sassone-Corsi P. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). as in this in to stress or other environmental cues, the glucocorticoid signal induction of Per1 with clock The to glucocorticoid to the in the Per1 promoter and Per1 expression not only that the to the in the Per1 promoter in but also a a of Per1 transcription in including be as a in for to the of this third pathway in Per1 are to and Sakakida for and to and for the also and for on the with
Yamamoto et al. (Wed,) studied this question.