title: Modulation of glucocorticoid receptor induction properties by core circadian clock proteins.
abstract: Glucocorticoid (GC) plays important roles in diverse physiological processes including metabolism and immune functions. While circadian control of GC synthesis and secretion is relatively well appreciated, circadian control of GC action within target tissues remains poorly understood. Here, we demonstrate that CLOCK/BMAL1, the core circadian clock components, reduces maximal GR transactivation (A(max)) as well as efficacy (EC₅₀) by a novel mechanism that requires binding to DNA and transactivation of target genes. Accordingly, we observe that PER1 and CRY1, the primary targets of CLOCK/BMAL1 action, reduce maximal GR transactivation while not affecting the efficacy. Moreover, we observe hyper-activations of GRE-dependent transcription in BMAL1- or PERs-deficient MEFs. In addition, endogenous GC target genes expression negatively correlates with the CLOCK/BMAL1 activity. Considering that GC sensitivity is widely implicated in human health and diseases, these results provide valuable insights into plethora of GC-related physiology and pathology.
authors.affiliation: Department of Neuroscience & Neurodegeneration Control Research Center, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Han
authors.affiliation: Department of Neuroscience & Neurodegeneration Control Research Center, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Yeon-Ju
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Physiology, Kyung Hee University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chang-Ju
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: Department of Neuroscience & Neurodegeneration Control Research Center, Kyung Hee University, Seoul, Republic of Korea; Department of Physiology, Kyung Hee University School of Medicine, Seoul, Republic of Korea. Electronic address: sehyung@khu.ac.kr.
authors.forename: Sehyung
authors.initials: S
authors.lastname: Cho
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D017440:Photoperiod; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D005938:Glucocorticoids; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D004247:DNA; D008156:Luciferases; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: Circadian; Clock genes; EC(50); Glucocorticoid receptor; Transactivation