Dominant-Negative CK2α Induces Potent Effects on Circadian Rhythmicity 英文参考文献.docVIP

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Dominant-Negative CK2α Induces Potent Effects on Circadian Rhythmicity 英文参考文献.doc

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Dominant-Negative CK2α Induces Potent Effects on Circadian Rhythmicity 英文参考文献

Dominant-NegativeCK2aInduces PotentEffectsonCircadianRhythmicity Elaine M.Smith1,Jui-Ming Lin1¤,Rose-Anne Meissner1,2,Ravi Allada1* 1 Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America, 2 Northwestern University Interdepartmental NeuroscienceProgram,NorthwesternUniversity,Evanston,Illinois,UnitedStatesofAmerica Circadianclocksorganizetheprecisetimingofcellularandbehavioralevents.InDrosophila,circadianclocksconsistof negative feedback loops in which the clock component PERIOD (PER) represses its own transcription. PER phosphorylation is a critical step in timing the onset and termination of this feedback. The protein kinase CK2 has beenlinkedtocircadiantiming,buttheimportanceofthiscontributionisunclear;itisnotcertainwhereandwhenCK2 actstoregulatecircadianrhythms.Todetermineitstemporalandspatialfunctions,adominantnegativemutantofthe catalytic alpha subunit, CK2aTik, was targeted to circadian neurons. Behaviorally, CK2aTik induces severe period lengthening (;33 h), greater than nearly all known circadian mutant alleles, and abolishes detectable free-running behavioral rhythmicity at high levels of expression. CK2aTik, when targeted to a subset of pacemaker neurons, generatesperiodsplitting,resultinginfliesexhibitingbothlongandnear24-hperiods.Thesebehavioraleffectsare evidentevenwhenCK2aTikexpressionisinducedonlyduringadulthood,implicatinganacuteroleforCK2afunctionin circadianrhythms.CK2aTik expressionresultsinreducedPERphosphorylation,delayednuclearentry,anddampened cycling with elevated trough levels of PER. Heightened trough levels of per transcript accompany increased protein levels,suggestingthatCK2aTik disturbsnegativefeedbackofPERonitsowntranscription.Takentogether,thesein vivodataimplicateacentralroleofCK2afunctionintimingPERnegativefeedbackinadultcircadianneurons. Citation:SmithEM,LinJ-M,MeissnerR-A,AlladaR(2008)Dominant-negativeCK2ainducespotenteffectsoncircadianrhythmicity.PLoSGenet4(1):e12.d