ADD1/SREBP-1c mediates insulin-induced gene expression linked to the MAP kinase pathway.
The aim of this study was to define the role of sterol regulatory element binding protein (SREBP)-1c, the human homologue to ADD1 (adipocyte determination- and differentiation-dependent factor 1), in insulin-induced gene expression. Transfection studies using SREBP-1-deficient cells and a LDL receptor promoter fragment containing the ADD1/SREBP-1c binding side showed that the effects of insulin and PDGF were abolished compared to control cells and completely reconstituted by overexpressing ADD1/SREBP-1c. Overexpression of upstream activators of MAP kinases, like MEKK1 or MEK1, demonstrated that ADD1/SREBP-1c-mediated effects of insulin and PDGF might be linked to the MAP kinase cascade. The recombinant N-terminal domain of ADD1/SREBP-1c was phosphorylated predominantly on serine and slightly on threonine residues by MAP kinases ERK1 and ERK2 in vitro. This was reversible by alkaline phosphatase. We conclude that ADD1/SREBP-1c mediates gene regulatory effects of insulin as well as PDGF and that this signalling is linked to the MAP kinase cascade.
Klinik II und Poliklinik für Innere Medizin der Universität zu Köln at the Center of Molecular Medicine, University of Cologne, Cologne, Germany.
J
J
Kotzka
D
D
Müller-Wieland
A
A
Koponen
D
D
Njamen
L
L
Kremer
G
G
Roth
M
M
Munck
B
B
Knebel
W
W
Krone
D000469:Alkaline Phosphatase / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D010769:Phosphothreonine / Q000032:analysis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D011973:Receptors, LDL; D011994:Recombinant Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D010769:Phosphothreonine; D010768:Phosphoserine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000469:Alkaline Phosphatase