title: CDK8-Cyclin C Mediates Nutritional Regulation of Developmental Transitions through the Ecdysone Receptor in Drosophila.
abstract: The steroid hormone ecdysone and its receptor (EcR) play critical roles in orchestrating developmental transitions in arthropods. However, the mechanism by which EcR integrates nutritional and developmental cues to correctly activate transcription remains poorly understood. Here, we show that EcR-dependent transcription, and thus, developmental timing in Drosophila, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability. We observed that cdk8 and cycC mutants resemble EcR mutants and EcR-target genes are systematically down-regulated in both mutants. Indeed, the ability of the EcR-Ultraspiracle (USP) heterodimer to bind to polytene chromosomes and the promoters of EcR target genes is also diminished. Mass spectrometry analysis of proteins that co-immunoprecipitate with EcR and USP identified multiple Mediator subunits, including CDK8 and CycC. Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain of EcR. These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR-dependent transcription. During the larval-pupal transition, the levels of CDK8 protein positively correlate with EcR and USP levels, but inversely correlate with the activity of sterol regulatory element binding protein (SREBP), the master regulator of intracellular lipid homeostasis. Likewise, starvation of early third instar larvae precociously increases the levels of CDK8, EcR and USP, yet down-regulates SREBP activity. Conversely, refeeding the starved larvae strongly reduces CDK8 levels but increases SREBP activity. Importantly, these changes correlate with the timing for the larval-pupal transition. Taken together, these results suggest that CDK8-CycC links nutrient intake to developmental transitions (EcR activity) and fat metabolism (SREBP activity) during the larval-pupal transition.
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Fu-Ning
authors.initials: FN
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Chemistry, University of Louisiana at Lafayette, Lafayette, Los Angeles, United States of America.
authors.forename: Wu
authors.initials: W
authors.lastname: Xu
authors.affiliation: Gene Regulatory Laboratory, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Ni
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Chemistry, University of Louisiana at Lafayette, Lafayette, Los Angeles, United States of America.
authors.forename: Liying
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Hao-Ching
authors.initials: HC
authors.lastname: Hsiao
authors.affiliation: Biological Mass Spectrometry Facility, Robert Wood Johnson Medical School and Rutgers, the State University of New Jersey, Frelinghuysen Road, Piscataway, New Jersey, United States of America.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Tianjin Radiation and Molecular Nuclear Medicine; Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Yani
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Alus M
authors.initials: AM
authors.lastname: Xiaoli
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America; Department of Biosciences, Rice University, Houston, Texas, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bondos
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Ji
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D056745:Cyclin C / Q000235:genetics / Q000378:metabolism*; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D026461:Ecdysteroids / Q000096:biosynthesis; D005260:Female; D005508:Food Deprivation; D005786:Gene Expression Regulation; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D009154:Mutation; D011987:Receptors, Steroid / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C503678:CycC protein, Drosophila; D056745:Cyclin C; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D026461:Ecdysteroids; D011987:Receptors, Steroid; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors; C066030:USP protein, Drosophila; C055469:ecdysone receptor; C498308:Cdk8 protein, Drosophila; D056850:Cyclin-Dependent Kinase 8