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