【摘 要】
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Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins.In mammals,mutations in casein kinase 1 (CK1) ε or δ can alter the circadian peri
【机 构】
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College of Fisheries and Life Science, Shanghai Ocean University, 999 Hucheng Road, Shanghai 201306,
【出 处】
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中国神经科学学会第九届全国学术会议暨第五届会员代表大会
论文部分内容阅读
Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins.In mammals,mutations in casein kinase 1 (CK1) ε or δ can alter the circadian period, but theparticular functions of the WT isoforms within the pacemaker remain unclear.We selectively targeted WT CK1ε and CK1δ using pharmacological inhibitors (PF-4800567 and PF-670462, respectively) alongside genetic knockout and knockdown to reveal that CK1 activity is essential to molecular pacemaking.Moreover, CK1δ is theprincipal regulator of the clock period: pharmacological inhibition ofCK1δ, but not CK1 ε, significantly lengthened circadian rhythms in locomotor activity in vivo and molecular oscillations in the suprachiasmatic nucleus (SCN) and peripheral tissue slices in vitro.Period lengthening mediated by CK 1δ inhibition was accompanied by nuclear retention of PER2 protein both in vitro and in vivo.Furthermore, phase mapping of the molecular clockwork in vitro showed that PF-670462 treatment lengthened the period in a phase-specific manner, selectively extending the duration of PER2-mediated transcriptional feedback.
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