BMAL1 shuttling controls transactivation and degradation of the CLOCK/BMAL1 heterodimer

Ilmin Kwon, Jiwon Lee, Seok Hoon Chang, Neon Cheol Jung, Byung Ju Lee, Gi Hoon Son, Kyungjin Kim, Kun Ho Lee

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Abstract

CLOCK and BMAL1 are bHLH-PAS-containing transcription factors that bind to Å-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.

Original languageEnglish
Pages (from-to)7318-7330
Number of pages13
JournalMolecular and cellular biology
Volume26
Issue number19
DOIs
Publication statusPublished - 2006 Oct 1
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kwon, I., Lee, J., Chang, S. H., Jung, N. C., Lee, B. J., Son, G. H., Kim, K., & Lee, K. H. (2006). BMAL1 shuttling controls transactivation and degradation of the CLOCK/BMAL1 heterodimer. Molecular and cellular biology, 26(19), 7318-7330. https://doi.org/10.1128/MCB.00337-06