本文／ＹＡ１０６１Ａ

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1 pp. PeriodPer CLOCKBMALPRIODCRY E-box bzip EBP Per PER peroxisome proliferator-activated receptor αpparα PPARα suprachiasmatic nucleus, SCN SCN SCN Molecular mechanism of rhythmic clock gene transcription, lipid metabolism and torpor Norio IshidaClock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and TechnologyAIST, Central, Higashi, Tsukuba, Ibaraki, Japan Period mperiod mperiod mperiod Timeless Timeout timeless mtimeless Cryptochrome mcryptochrome mcryptochrome ClockJrk Clock NPASMoP Cycle BmalMOP BmalMOP doubletime casein kinase I ε casein kinase I δ shaggy GSKβ protein phosphatase A slimb vrille β -TrCP, β -TpCP EBP

2 period periodperiodperiod CryCryClockBmalcasein kinase I εglycogen synthase kinaseβgsk-β β -TrCPβ -TrCPEBP mrna Per SCN SCN SCN SCN Erwin Schrödinger CLOCKBMAL PE- RIODCRYPTOCHROME SCN Shaggy period PERIOD period R. Konoplka S. Benzer Benzer

3 Period DNA periodrper Period per perper per per per per per per per SCN BMAL per rper rper COS PER CRY CRY rper TG rper TG rper rper SCN PER PERIOD CRY rper SCN PER glycogen synthase kinase-βgsk-β GSK-β PER LiCl LiCl GSK- β PER rper rper ASPSDSPS

4 ASPS hper IεCKIε N PER PER hper Iε DSPS per PER Clock period Per per mrna CACGTT E-box PER vrille bzip EBP mper AB EBP ABB-site per ChIP B-site A-siteB-site E-box per C E E-box B-site in vitro A-site E-box CLOCKBMAL PERCRY per EBP PER CRY PERCRY CLOCKBMAL EBP B-siteD-box Mdr P ACYPA cholesterol α-hydroxylase Cypα EBP EBP ClockCryCry SCN SCN SCN ACTH perebp wee Dec PPARα SCN SCN SCN SCN

5 A mper EBP E; E-box B A-site B-site B-site C Per EBP PERIOD CRY Britman SCN SCN SCN P. Sassone-Corsi Per

6 MEF Per MEF clock clock clock MEF SCN SCN obese clock obese clock clock obese obese clock obese clock obese clock F. Turek clock clock clock PPARα β-oxidation PPARα PPARα E- box clockbmal clock PPARα clock PPARα rev-erbα PAI- ApoClll Clock T-ChoTG obob clkclk

7 Heme PPAR-α FGF PAI-; plasminogen activator inhibition, apociii; apolipoprotein CIII PPARα PPARα hh hh PPARα a DSPS b PPARα c NPY NPY Y B PPARα FGF

8 DSPS period

9 DNA Dunlap, J.C.Cell,,. Ishida, N., Kaneko, M., & Allada, R.Proc. Natl. Acad. Sci. USA,,. Sakamoto, K., Nagase, T., Fukui, H., Horikawa, K., Okada, T., Tanaka, H., Sato, K., Miyake, Y., Ohara, O., Kako, K., & Ishida, N.J. Biol. Chem.,,. Konopka, R.J. & Benzer, S.Proc. Natl. Acad. Sci. USA,,. Lowrey,P.L.&Takahashi,J.S.Annu. Rev. Genomics Hum Genet.,,. Miyazaki, K., Mesaki, M., & Ishida, N.Mol. Cell. Biol.,,. Miyazaki, K., Wakabayashi, M., Chikahisa, S., Sei, H., Ishida, N.Genes Cells,,. Iidaka, C., Miyazaki, K., Akaike, T., & Ishida, N.J. Biol. Chem.,,. Yoo, S.H., Ko, C.H., Lowrey, P.L., Buhr, F.D., Song, E.J., Chang, S., Yoo, O.J., Yamazaki, S., Lee, C., & Takahashi, J.S. Proc. Natl. Acad. Sci. USA,,. Akashi, M., Ichise, T., Mamine, T., Takumi, T.Mol. Biol. Cell,,. Ohno, T., Onishi, Y., & Ishida, N.Nucleic Acids Res.,,. Ueda, H.R., Chen, W., Adachi, A., Wakamatsu, H., Hayashi, S., Takasugi, T., Nagano, M., Nakahama, K., Suzuki, Y., Sugano, S., Iino, M., Shigeyoshi, Y., & Hashimoto, S. Nature,,. Ohno, T., Onishi, Y., & Ishida, N.Biochem. Biophys. Res. Com.,,. Kotaka, M., Onishi, Y., Ohno, T., Akaike, T., & Ishida, N. Neurosci. Res.,,. Takiguchi, T., Tomita, M., Matsunaga, N., Nakagawa, H., Koyanagi, S., & Ohdo, S.Pharmacogenet Genomics,,. Noshiro, M., Usui, E., Kawamoto, T., Kubo, H., Fujimoto, K., Furukawa, M., Honma, S., Makishima, M., Honma, K., & Kato, Y.J. Biol. Rhythms,,. Oishi, K., Miyazaki, K., Kadota, K., Kikuno, R., Nagase, T., Atsumi, G., Ohkura, N., Azama, T., Mesaki, M., Yukimasa, S., Kobayashi, H., Iitaka, C., Umehara, T., Horikoshi, M., Kudo, T., Shimizu, Y., Yano, M., Monden, M., Machida, K., Matsuda, M., Horie, S., Todo, T., & Ishida, N.J. Biol. Chem,,. Oishi, K., Sakamoto, K., Okada, T., Nagase, T., & Ishida, N. Neurosci. Lett.,:. Oishi, K., Amagai, N., Shirai, H., Kadota, K., Ohkura, N., & Ishida, N.DNA Res.,:. Guo, H., Brewer, J. M., & Bittman, E.L.Proc. Natl. Acad. Sci. USA,:. Pando, M.P., Morse, D., & S-Corsi, P.Cell,:. Oishi, K., Ohkura, N., Wakabayashi, M., Shirai, H., Sato, K., Matsuda, J., & Ishida, N.J. Thromb. Haemos., :. Turek, F.W., Joshu, C., Kohsaka, A., Lin, E., Ivanova, G., McDearmon, E., Laposky, A., Losee-Olson, S., Easton, A., Jensen, D., Eckel, R.H., Takahashi, J.S., & Bass, J. Science,:. Ishida, N.Neurosci. Res.,:. Oishi, K., Atsumi, G., Sugiyama, S., Kodomari, I., Kasamatsu, M., Machida, K., Ishida, N.FEBS Lett.,:. Staels, B.Nat. Med.,:. Oishi, K., Shirai, H., Ishida, N.Biochem. J.,:.,. Shirai, H., Oishi, K., Kudo, T., Shibata, S., Ishida, N. Biochem. Biophys. Res. Commun.,:. Oishi, K., Shirai, H., Ishida, N.Neuro Report,,. Chikahisa, S., Tominaga, K., Kawai, T., Kitaoka, K., Oishi, K., Ishida, N., Rokutan, K., Sei, H.Endocrinology,,. Oishi, K., Uchida, D., Ishida, N.FEBS Lett.,,. Onishi, Y., Hanai, S., Ohno, T., Hara, Y., Ishida, N. Mol. Cell Biol.,,.

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