Involvement of peroxisome proliferator-activated receptor gamma in gonadal steroidogenesis and steroidogenic acute regulatory protein expression.
Peroxisome proliferator-activated receptor (PPAR) gamma belongs to the PPAR family of nuclear transcription factors whose ligands, such as eicosanoids, fatty acids and prostaglandins, are known to affect gonadal function. Although several of these enhance the expression of the steroidogenic acute regulatory protein (STAR) and steroid production, the role of PPARgamma in regulating STAR-mediated steroidogenesis remains unclear. In the present study, we used ciglitazone to selectively activate PPARgamma and examine its role in STAR-mediated steroidogenesis in immortalised KK1 mouse granulosa cells and MA-10 mouse Leydig tumour cells. Cotreatment with both dibutyryl-cAMP and ciglitazone revealed a dose-dependent, significant increase in progesterone synthesis, Star promoter activity, Star mRNA and STAR protein relative to either compound alone. The overexpression of PPARgamma further increased Star-promoter activity. The ciglitazone-induced activity of the Star-promoter appears to be mediated through the cAMP-response element half-sites located within its proximal 151 bp. Combined treatment with ciglitazone and dibutyryl-cAMP significantly increased the expression and activity of transcriptional pathways impacted by the activator protein-1 family member c-JUN. The present study demonstrates that ciglitazone and dibutyryl-cAMP synergistically enhance STAR expression in MA-10 and KK1 cells. Ciglitazone-activated PPARgamma appears to increase the sensitivity of Leydig and granulosa cells to cAMP stimulation, possibly via upregulation of c-JUN expression.
Kowalewski
Mariusz P
MP
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Dyson
Matthew T
MT
Manna
Pulak R
PR
Stocco
Douglas M
DM
D000818:Animals; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003563:Cyclic CMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D054339:Steroidogenic Factor 1 / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C492004:Creb1 protein, mouse; C497411:Crem protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D047495:PPAR gamma; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D054339:Steroidogenic Factor 1; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D051786:Cyclic AMP Response Element Modulator; D003563:Cyclic CMP; D011374:Progesterone; C053441:dibutyryl cyclic-3',5'-cytidine monophosphate; D020928:Mitogen-Activated Protein Kinases; C039671:ciglitazone