Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity

May 29, 2002Proceedings of the National Academy of Sciences of the United States of America

Two-way control of daily rhythm genes by CREB signaling and the CLOCK/BMAL1 system

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Abstract

All three mouse Period (Per) gene promoters respond to the CLOCK/BMAL1 complex, but only mPer1 and mPer2 contain elements that respond to cAMP signaling.

Three Period genes exist in mice: mPer1, mPer2, and mPer3, with mPer1 and mPer2 being light-responsive.
All mPer promoters contain E-boxes that interact with the CLOCK/BMAL1 protein complex.
Only mPer1 and mPer2 promoters possess cAMP-responsive elements that bind to the CRE-binding protein.
The mPer1 promoter requires both cAMP and mitogen-activated protein kinase pathways for activation.
Activation of mPer promoters by CLOCK/BMAL1 occurs independently of the integrity of the cAMP-responsive elements.

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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.

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Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity

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