title: AP-1 is a component of the transcriptional network regulated by GSK-3 in quiescent cells.
abstract: BACKGROUND
  The protein kinase GSK-3 is constitutively active in quiescent cells in the absence of growth factor signaling. Previously, we identified a set of genes that required GSK-3 to maintain their repression during quiescence. Computational analysis of the upstream sequences of these genes predicted transcription factor binding sites for CREB, NFκB and AP-1. In our previous work, contributions of CREB and NFκB were examined. In the current study, the AP-1 component of the signaling network in quiescent cells was explored.
  
  
  RESULTS
  Using chromatin immunoprecipitation analysis, two AP-1 family members, c-Jun and JunD, bound to predicted upstream regulatory sequences in 8 of the 12 GSK-3-regulated genes. c-Jun was phosphorylated on threonine 239 by GSK-3 in quiescent cells, consistent with previous studies demonstrating inhibition of c-Jun by GSK-3. Inhibition of GSK-3 attenuated this phosphorylation, resulting in the stabilization of c-Jun. The association of c-Jun with its target sequences was increased by growth factor stimulation as well as by direct GSK-3 inhibition. The physiological role for c-Jun was also confirmed by siRNA inhibition of gene induction.
  
  
  CONCLUSIONS
  These results indicate that inhibition of c-Jun by GSK-3 contributes to the repression of growth factor-inducible genes in quiescent cells. Together, AP-1, CREB and NFκB form an integrated transcriptional network that is largely responsible for maintaining repression of target genes downstream of GSK-3 signaling.
authors.affiliation: Department of Biology, Boston University, Boston, Massachusetts, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Tullai
authors.forename: Silvia
authors.initials: S
authors.lastname: Tacheva
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Owens
authors.forename: Julie R
authors.initials: JR
authors.lastname: Graham
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Cooper
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; C559371:JunD protein, human; D008301:Maleimides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; C417521:SB 216763; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3