title: Mechanisms of FOXC2- and FOXD1-mediated regulation of the RI alpha subunit of cAMP-dependent protein kinase include release of transcriptional repression and activation by protein kinase B alpha and cAMP.
abstract: We have reported recently that mice overexpressing the forkhead/winged helix transcription factor FOXC2 are lean and show increased responsiveness to insulin due to sensitization of the beta-adrenergic cAMP-PKA(+) pathway and increased levels of the RI alpha subunit of cAMP-dependent protein kinase (PKA) (Cederberg, A., Grønning, L. M., Ahren, B., Taskén, K., Carlsson, P., and Enerbäck, S. (2001) Cell 106, 563-573). In this present study, we reveal that FOXC2 and a related factor, FOXD1, specifically activate the 1b promoter of the RI alpha gene in adipocytes and testicular Sertoli cells, respectively. By deletional mapping, we discovered two different mechanisms by which the Fox proteins activated expression from the RI alpha 1b promoter. In 3T3-L1 adipocytes, an upstream region represses promoter activity under basal conditions. Bandshift experiments indicate that overexpression of FOXC2 promotes the release of a potential repressor from this region. In Sertoli cells, sequences downstream of the transcription start sites mediate the activating effect of FOXD1, and protein kinase B alpha/Akt1 strongly induces this effect. Furthermore, we show that an inactive FOXD1 mutant lowers the cAMP-mediated induction of the RI alpha 1b reporter construct. In summary, winged helix transcription factors of the FOXC/FOXD families function as regulators of the RI alpha subunit of PKA and may integrate hormonal signals acting through protein kinase B and cAMP in a cell-specific manner.
authors.affiliation: Department of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Dahle
authors.forename: Line M
authors.initials: LM
authors.lastname: Grønning
authors.forename: Anna
authors.initials: A
authors.lastname: Cederberg
authors.forename: Heidi Kiil
authors.initials: HK
authors.lastname: Blomhoff
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Taskén
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D012708:Sertoli Cells / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D000071161:Forkhead Box Protein O1
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D008156:Luciferases; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C489562:Foxd1 protein, mouse; C082078:mesenchyme fork head 1 protein; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C494920:Akt1 protein, rat