title: PER2 Differentially Regulates Clock Phosphorylation versus Transcription by Reciprocal Switching of CK1ε Activity.
abstract: Casein kinase 1ε (CK1ε) performs key phosphorylation reactions in the circadian clock mechanism that determine period. We show that the central clock protein PERIOD2 (PER2) not only acts as a transcriptional repressor but also inhibits the autoinactivation of CK1ε, thereby promoting CK1ε activity. Moreover, PER2 reciprocally regulates CK1ε's ability to phosphorylate other substrates. On output pathway substrates (e.g., P53), PER2 inhibits the activity of CK1ε. However, in the case of central clock proteins (e.g., CRYPTOCHROME2), PER2 stimulates the CK1ε-mediated phosphorylation of CRY2. CK1ε activity is temperature compensated on the core clock substrate CRY2 but not on output substrates, for example, the physiological output protein substrate P53 and its nonphysiological correlate, bovine serum albumin (BSA). These results indicate heretofore unrecognized pivotal roles of PER2; it not only regulates the central transcription/translation feedback loop but also differentially controls kinase activity CK1ε in its phosphorylation of central clock (e.g., CRY2) versus output (e.g., P53) substrates.
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee.
authors.forename: Ximing
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee.
authors.forename: Carl Hirschie
authors.initials: CH
authors.lastname: Johnson
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D048149:Casein Kinase 1 epsilon / Q000378:metabolism*; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D056931:Cryptochromes / Q000378:metabolism; D006801:Humans; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D056931:Cryptochromes; D056950:Period Circadian Proteins; D012097:Repressor Proteins; D056926:CLOCK Proteins; D048149:Casein Kinase 1 epsilon
keywords: CK1ε; CRYPTOCHROME; PERIOD; circadian; clock