{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:36:13Z","timestamp":1781102173081,"version":"3.54.1"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1996,11,26]]},"abstract":"<jats:p>\n                    Transcription factor cAMP-responsive element modulator (CREM) plays\n a key physiological and developmental role within the\n hypothalamic-pituitary-gonadal axis. The use of an alternative,\n intronic promoter within the CREM gene is responsible for the\n production of a cAMP-inducible repressor, inducible cAMP early\n repressor (ICER). ICER negatively autoregulates the ICER promoter, thus\n generating a feedback loop. We have previously documented a striking,\n clock-driven circadian fluctuation of CREM expression in the pineal\n gland. Oscillating ICER levels tightly correlate with fluctuations in\n the synthesis of the pineal hormone melatonin, whose production is also\n driven by the endogenous clock. Melatonin in turn regulates\n the hypothalamic-pituitary axis. The enzyme serotonin\n                    <jats:italic>N<\/jats:italic>\n                    -acetyltransferase (NAT) catalyzes the rate limiting\n step in melatonin synthesis. Thus, oscillations in NAT levels determine\n the circadian synthesis of melatonin. Here we demonstrate that NAT\n expression is dramatically increased in CREM-deficient mice that we\n have generated by homologous recombination. Characterization of the NAT\n promoter shows the presence of a ICER binding site. In addition,\n transfection studies show that ICER powerfully represses NAT\n transcription. Our results implicate CREM as a central regulator of\n output functions of the clock. Indeed, CREM acts as a key regulator of\n oscillatory hormonal synthesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.93.24.14140","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:16Z","timestamp":1027679656000},"page":"14140-14145","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":129,"title":["Transcriptional control of circadian hormone synthesis via the CREM feedback\u2009loop"],"prefix":"10.1073","volume":"93","author":[{"given":"Nicholas\u2009S.","family":"Foulkes","sequence":"first","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire\r et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France; and\r Departments of Neuroscience, Pharmacology and\r Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns\r Hopkins University School of Medicine, 725 North  Wolfe Street,\r Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimo","family":"Borjigin","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire\r et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France; and\r Departments of Neuroscience, Pharmacology and\r Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns\r Hopkins University School of Medicine, 725 North  Wolfe Street,\r Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomon\u2009H.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire\r et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France; and\r Departments of Neuroscience, Pharmacology and\r Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns\r Hopkins University School of Medicine, 725 North  Wolfe Street,\r Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Sassone-Corsi","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire\r et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, France; and\r Departments of Neuroscience, Pharmacology and\r Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns\r Hopkins University School of Medicine, 725 North  Wolfe Street,\r Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1996,11,26]]},"reference":[{"key":"e_1_3_2_1_2","volume-title":"Endocrinology and Metabolism","author":"Felig P","year":"1987","unstructured":"P Felig, J D Baxter, A E Broadus, L A Frohman Endocrinology and Metabolism (McGraw\u2013Hill, New York, 1987)."},{"key":"e_1_3_2_2_2","volume-title":"Endocrine Rhythms","author":"Krieger D T","year":"1979","unstructured":"D T Krieger Endocrine Rhythms (Raven, New York, 1979)."},{"key":"e_1_3_2_3_2","first-page":"217","volume-title":"Suprachiasmatic Nucleus: The Mind\u2019s Clock","author":"Karsch F J","year":"1991","unstructured":"F J Karsch, J I Woodfill, B Malpaux, J I Robinson, N L Wayne Suprachiasmatic Nucleus: The Mind\u2019s Clock, eds D C Klein, R Y Moore, S M Reppert (Oxford Univ. Press, New York), pp. 217\u2013232 (1991)."},{"key":"e_1_3_2_4_2","first-page":"201","volume-title":"Melatonin and the Mammalian Pineal Gland","author":"Arendt J","year":"1995","unstructured":"J Arendt Melatonin and the Mammalian Pineal Gland (Chapman & Hall, London), pp. 201\u2013285 (1995)."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.5.1824"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3881822"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/1043-2760(91)90055-R"},{"key":"e_1_3_2_8_2","first-page":"38","volume-title":"Photoperiodism, Melatonin, and the Pineal Gland","author":"Klein D C","year":"1985","unstructured":"D C Klein Photoperiodism, Melatonin, and the Pineal Gland, eds D Evered, S Clark (Pitman, London), pp. 38\u201356 (1985)."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.184.4144.1341"},{"key":"e_1_3_2_10_2","first-page":"691","volume-title":"Handbook of Experimental Pharmacology","author":"Zatz M","year":"1982","unstructured":"M Zatz Handbook of Experimental Pharmacology, eds J W Kebabian, J A Nathanson (Springer, Berlin), pp. 691\u2013710 (1982)."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cb.11.110195.002035"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2974179"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90013-5"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1993.tb06068.x"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)55078-X"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90503-Q"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/355080a0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90167-P"},{"key":"e_1_3_2_19_2","first-page":"1502","volume":"7","author":"Delmas V","year":"1993","unstructured":"V Delmas, F van der Hoorn, B Mellstr\u00f6m, B J\u00e9gou, P Sassone-Corsi Mol Endocrinol 7, 1502\u20131514 (1993).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/362264a0"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90532-U"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/365314a0"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.21.9633"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.23.10673"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(94)00040-0"},{"key":"e_1_3_2_26_2","first-page":"706","volume":"9","author":"Stehle J H","year":"1995","unstructured":"J H Stehle, N S Foulkes, P P\u00e9vet, P Sassone-Corsi Mol Endocrinol 9, 706\u2013716 (1995).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(81)90644-5"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.1985.tb00628.x"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/381083a0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/378783a0"},{"key":"e_1_3_2_31_2","first-page":"3305","volume":"9","author":"Foletta V C","year":"1994","unstructured":"V C Foletta, M H Sonobe, T Suzuki, T Endo, H Iba, D R Cohen Oncogene 9, 3305\u20133311 (1994).","journal-title":"Oncogene"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/15.13.5490"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/19.9.2499"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/380159a0"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.1989.tb00667.x"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3941912"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.45.27319"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb08560.x"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/380162a0"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5242.1681"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/282094a0"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.4.2319"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.19.6119"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8128244"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8284676"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90415-4"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.93.24.14140","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T15:03:22Z","timestamp":1649862202000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.93.24.14140"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1996,11,26]]},"references-count":46,"journal-issue":{"issue":"24","published-print":{"date-parts":[[1996,11,26]]}},"alternative-id":["10.1073\/pnas.93.24.14140"],"URL":"https:\/\/doi.org\/10.1073\/pnas.93.24.14140","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1996,11,26]]},"assertion":[{"value":"1996-09-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1996-11-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}