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Molecular and Cellular Biology, October 2006, p. 7318-7330, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00337-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

BMAL1 Shuttling Controls Transactivation and Degradation of the CLOCK/BMAL1 Heterodimer

Ilmin Kwon,1 Jiwon Lee,1 Seok Hoon Chang,1 Neon Cheol Jung,1 Byung Ju Lee,2 Gi Hoon Son,1 Kyungjin Kim,1* and Kun Ho Lee1*

School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea,1 Department of Biological Sciences, University of Ulsan, Ulsan 680-749, South Korea2

Received 24 February 2006/ Returned for modification 5 May 2006/ Accepted 10 July 2006

CLOCK and BMAL1 are bHLH-PAS-containing transcription factors that bind to E-box elements and are indispensable for expression of core circadian clock components such as the Per and Cry genes. A key step in expression is the heterodimerization of CLOCK and BMAL1 and their accumulation in the nucleus with an approximately 24-h periodicity. We show here that nucleocytoplasmic shuttling of BMAL1 is essential for transactivation and for degradation of the CLOCK/BMAL1 heterodimer. Using serial deletions and point mutants, we identified a functional nuclear localization signal and Crm1-dependent nuclear export signals in BMAL1. Transient-transfection experiments revealed that heterodimerization of CLOCK and BMAL1 accelerates their turnover, as well as E-box-dependent clock gene transcription. Moreover, in embryonic mouse fibroblasts, robust transcription of Per2 is tightly associated with massive degradation of the CLOCK/BMAL1 heterodimer. CRY proteins suppressed this process during the transcription-negative phase and led to nuclear accumulation of the CLOCK/BMAL1 heterodimer. Thus, these findings suggest that the decrease of BMAL1 abundance during the circadian cycle reflects robust transcriptional activation of clock genes rather than inhibition of BMAL1 synthesis.

* Corresponding author. Mailing address for Kun Ho Lee: School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea. Phone: 82-2-873-6690. Fax: 82-2-872-1993. E-mail: leekho{at}snu.ac.kr. Mailing address for Kyungjin Kim: Neuroendocrine Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea. Phone: 82-2-880-6694. Fax: 82-2-884-6560. E-mail: kyungjin{at}snu.ac.kr.

Molecular and Cellular Biology, October 2006, p. 7318-7330, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00337-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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