Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity.
Circadian rhythmicity in mammals is under the control of a molecular pacemaker constituted of clock gene products organized in transcriptional autoregulatory loops. Phase resetting of the clock in response to light involves dynamic changes in the expression of several clock genes. The molecular pathways used by light to influence pacemaker-driven oscillation of clock genes remain poorly understood. We explored the functional integration of both light- and clock-responsive transcriptional regulation at the promoter level of the Period (Per) genes. Three Per genes exist in the mouse. Whereas mPer1 and mPer2 are light-inducible in clock neurons of the hypothalamic suprachiasmatic nucleus, mPer3 is not. We have studied the promoter structure of the three mPer genes and compared their regulation. All three mPer promoters contain E-boxes and respond to the CLOCK/brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) heterodimer. On the other hand, only mPer1 and mPer2 promoters contain bona fide cAMP-responsive elements (CREs) that bind CRE-binding protein (CREB) from suprachiasmatic nucleus protein extracts. The mPer1 promoter is responsive to synergistic activation of the cAMP and mitogen-activated protein kinase pathways, a physiological response that requires integrity of the CRE. In contrast, activation of mPer promoters by CLOCK/BMAL1 occurs regardless of an intact CRE. Altogether, these results constitute strong evidence that CREB acts as a pivotal endpoint of signaling pathways for the regulation of mPer genes. Our results reveal that signaling-dependent activation of mPer genes is distinct from the CLOCK/BMAL1-driven transcription required within the clock feedback loop.
Travnickova-Bendova
Zdenka
Z
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale-Université Louis Pasteur, B.P. 10142, 67404 Illkirch-Strasbourg, France.
Cermakian
Nicolas
N
Reppert
Steven M
SM
Sassone-Corsi
Paolo
P
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000502:physiology*; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002822:Choriocarcinoma; D002940:Circadian Rhythm; D003001:Cloning, Molecular; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics*; D009897:Optic Chiasm / Q000502:physiology*; D009928:Organ Specificity; D056950:Period Circadian Proteins; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D017384:Sequence Deletion; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C539022:PER1 protein, human; C421902:PER2 protein, human; C512644:PER3 protein, human; C539023:Per1 protein, mouse; C539024:Per1 protein, rat; C513312:Per2 protein, mouse; C513311:Per2 protein, rat; C512645:Per3 protein, mouse; C512646:Per3 protein, rat; C538943:CLOCK protein, human; C538944:Clock protein, mouse; C538945:Clock protein, rat