BMAL1 Shuttling Controls Transactivation and Degradation of the CLOCK/BMAL1 Heterodimer
| Autor: | Gi Hoon Son, Ilmin Kwon, Neon Cheol Jung, Byung Ju Lee, Seok Hoon Chang, Jiwon Lee, Kyungjin Kim, Kun Ho Lee |
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| Rok vydání: | 2006 |
| Předmět: |
Transcriptional Activation
Cytoplasm endocrine system Transcription Genetic Molecular Sequence Data Nuclear Localization Signals Circadian clock CLOCK Proteins E-box Biology Models Biological Mice Transactivation Basic Helix-Loop-Helix Transcription Factors Animals Humans Amino Acid Sequence Nuclear export signal Molecular Biology Cells Cultured Cell Nucleus Nuclear Export Signals ARNTL Transcription Factors Ubiquitin Articles Cell Biology Molecular biology Circadian Rhythm Protein Structure Tertiary Cell biology PER2 CLOCK Protein Transport NIH 3T3 Cells Trans-Activators Mutant Proteins Dimerization Protein Processing Post-Translational HeLa Cells |
| Zdroj: | Molecular and Cellular Biology. 26:7318-7330 |
| ISSN: | 1098-5549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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