Sathyanarayanan Sriram, Zheng Xiangzhong, Xiao Rui, Sehgal Amita
Howard Hughes Medical Institute, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Cell. 2004 Feb 20;116(4):603-15. doi: 10.1016/s0092-8674(04)00128-x.
The posttranscriptional mechanisms that control the cycling of circadian clock protein levels are not known. Here we demonstrate a role for protein phosphatase 2A (PP2A) in the cyclic expression of the PER protein. PP2A regulatory subunits TWS and WDB target PER and stabilize it in S2 cells. In adult fly heads, expression of tws cycles robustly under control of the circadian clock. Hypomorphic tws mutants show delayed accumulation of PER, while overexpression of tws in clock neurons produces shorter, weaker rhythms. Reduction of PP2A activity reduces PER expression in central clock neurons and results in long periods and arrhythmia. In addition, overexpression of the PP2A catalytic subunit results in loss of behavioral rhythms and constitutive nuclear expression of PER. PP2A also affects PER phosphorylation in vitro and in vivo. We propose that the posttranslational mechanisms that drive cycling of PER require the rhythmic expression of PP2A.
控制昼夜节律钟蛋白水平循环的转录后机制尚不清楚。在此，我们证明了蛋白磷酸酶2A（PP2A）在PER蛋白循环表达中的作用。PP2A调节亚基TWS和WDB靶向PER并使其在S2细胞中稳定。在成年果蝇头部，tws的表达在昼夜节律钟的控制下强烈循环。低表达的tws突变体显示PER的积累延迟，而在时钟神经元中过表达tws会产生更短、更弱的节律。PP2A活性的降低会减少中央时钟神经元中PER的表达，并导致长时间和心律失常。此外，PP2A催化亚基的过表达会导致行为节律丧失和PER的组成型核表达。PP2A在体外和体内也会影响PER的磷酸化。我们提出，驱动PER循环的翻译后机制需要PP2A的节律性表达。
