Reduced phosphorylation of transcription factor Elk-1 in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance.
The effect of insulin and growth factor mediated signaling to gene regulation was investigated in cultured fibroblasts of a patient with a premature aging syndrome (metageria) and severe insulin resistance. Insulin receptor structure and function as well as major pathways activated by insulin, i.e. phosphatidyl inositol-3 kinase (PI-3 K) cascade or mitogen-activated protein kinase (MAPK) cascades, were functional. Inducibility of the proto-oncogene cfos, a representative endpoint of signaling pathways related to gene expression, by growth factors or insulin was reduced in patient cells. This reduced induction persisted in cfos promoter reporter gene studies indicating that the post receptor defect is localized proximal to the cfos promoter itself. Abundances of the transcription factors Elk-1 and SRF being major players in coupling of MAPKs to cfos promoter activation were not altered. However, basal and inducible phosphorylation of Elk-1 was impaired. In addition, basal and stimulated transcriptional activity mediated by Elk-1 was almost abolished in patient cells. Therefore these results identify a post receptor defect in cFos induction, which appears to be related to a functional alteration of Elk-1. A possible relation of this signal transduction defect to the specific premature aging syndrome remains to be elucidated.
Knebel
B
B
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine University Düsseldorf, Member of the Leibniz Society, Düsseldorf, Germany.
Avci
H
H
Bullmann
C
C
Kotzka
J
J
Müller-Wieland
D
D
D000328:Adult; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D010766:Phosphorylation; D011371:Progeria / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D048049:Extracellular Signal-Regulated MAP Kinases