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.
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