Peroxisome proliferator-activated receptor gamma regulates expression of signal transducer and activator of transcription 5A.
Signal transducer and activator of transcription 5A (STAT5A) has been shown to be important for terminal differentiation of mammary epithelial cells. In order to understand regulation of expression of STAT5A, the 5' end of the mouse Stat5a gene was isolated. Putative regulatory elements was searched for and several peroxisome proliferator response elements (PPREs) were found, one with high (12/13 nucleotides) and three with less (8-10/13) similarity to the reported consensus sequence. Mouse mammary epithelial HC11 cells were treated with peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, the thiazolidinedione (TZD) troglitazone, and an increase in STAT5A protein expression was seen. The 5' flank of Stat5a gene was cloned in a luciferase reporter vector. A concentration dependent activation of the STAT5A-luciferase reporter was detected, when transiently transfected HC11 cells were treated with TZD. The activation could be inhibited by treatment with a PPARgamma antagonist. It has earlier been shown that epidermal growth factor (EGF) induces MAPK phosphorylation of PPARgamma resulting in a less transcriptionally active receptor. In HC11 cells, EGF inhibited TZD induced STAT5A-reporter activity suggesting that our previously reported EGF-mediated suppression of STAT5A expression is mediated in all or partly through inhibition of PPARgamma activity. Furthermore, the MEK inhibitor PD98059 inhibited the EGF effect. All together, data presented suggest that PPARgamma participates in regulation of STAT5A expression.
Olsen
Hanne
H
Department of Medical Nutrition, Karolinska Institutet, NOVUM, S-141 86 Huddinge, Sweden.
Haldosén
Lars-Arne
LA
D024506:5' Flanking Region / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D008024:Ligands; D008156:Luciferases; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D002839:Chromans; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D008024:Ligands; D047495:PPAR gamma; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D045162:Thiazolidinediones; D004815:Epidermal Growth Factor; D008156:Luciferases; D048369:MAP Kinase Kinase 1; D000077288:Troglitazone