東京大学グローバルCOE『統合生命学』特別セミナー
東京大学 大学院理学系研究科 生物化専攻セミナー
演者:Dr. Paul E. Hardin
   Department of Biology and Center for Research on Biological Clocks, Texas A&M University, USA
演題:Regulation of transcriptional feedback within the Drosophila circadian clock
日時:平成20 年7月15 日(火)16:30 ~ 18:00
場所:東京大学理学部3 号館3 階327 号室

Transcriptional activation by CLOCK-CYC (CLK-CYC) heterodimers and feedback repression by PERIOD-TIMELESS (PER-TIM) heterodimers are essential for circadian oscillator function in Drosophila. The function of these transcriptional regulators is regulated by post-translational modifications that alter DNA binding, stability and chromatin modifications. We find that binding of CLK-CYC heterodimers containing hypophosphorylated CLK to E-box elements promotes chromatin modifications that enhance transcriptional activation of per, tim and other circadian oscillator components. PER protein then begins to accumulate, but in a delayed fashion due to DOUBLE-TIME (DBT) dependent phosphorylation and subsequent stabilization by TIM binding. PER-TIM-DBT complexes then enter the nucleus and bind to CLK-CYC, thus promoting the hyperphosphorylation of CLK, loss of CLK-CYC E-box binding, and transcriptional repression. Recent experiments using the PERΔ mutant, which is unable to bind DBT, and hypomorphic dbtar and dominant negative dbtK/R mutants suggest that DBT acts as a bridge to recruit other kinase(s) into PER-TIM-DBT-CLK-CYC complexes. Once these kinases enter DBT-PER-CLK complexes they phosphorylate PER and CLK, thereby promoting transcriptional repression. Subsequent phosphorylation of PER and CLK by DBT promotes PER and CLK degradation, thereby relieving transcriptional repression.

References:
Yu, W., H. Zheng, J. H. Houl and P. E. Hardin (2006) PER dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription. Genes Dev. 20, 723-733.

Kim, E. Y., H. W, Ko, W. Yu, P. E. Hardin and I. Edery (2007) A DOUBLETIME kinase binding domain on the Drosophila PERIOD protein is essential for its hyperphosphorylation, transcriptional repression and circadian clock function. Mol. Cell. Biol. 27, 5014-5028.

世話人:理学系 生物化学専攻 深田 吉孝