TGF-beta inhibits CYP17 transcription in H295R cells acting via activin receptor-like kinase 5.
OBJECTIVE
Transforming growth factor beta (TGF-beta) is a potent inhibitor of 17alpha-hydroxylase/17,20 lyase activity and CYP17 gene expression. We investigated the mechanism how CYP17 is inhibited by TGF-beta in adrenocortical cells.


METHODS
H295R cells were culture and incubated with TGF-beta, transcription inhibitor (DRB), activin receptor-like kinase 5 ALK5 (TbetaRII) inhibitor (SB431542), mitogen activated kinases inhibitors (PD98059 and SB203580), subsequently using reverse transcription and quantitative PCR (RT-qPCR) we determined CYP17 expression.


RESULTS
TGF-beta significantly decreased the level of cytochrome P450c17 mRNA and this inhibitory effect of TGF-beta on CYP17 expression required activin receptor-like kinase 5 (ALK5) and on-going transcription. Mitogen activated kinases MEK1 and p38 MAPK are not involved it the inhibitory effect of TGF-beta on CYP17 expression.


CONCLUSIONS
We concluded that the TGF-beta-dependent decrease of 17alpha-hydroxylase/17,20 lyase activity in the H295R cells is caused by inhibition of CYP17 transcription and is mediated by the ALK5 receptor.
Derebecka-Holysz
Natalia
N
Department of Biochemistry and Molecular Biology, University of Medical Sciences, 60-781, Poznan, Poland.
Lehmann
Tomasz P
TP
Holysz
Marcin
M
Trzeciak
Wieslaw H
WH
D029404:Activin Receptors / Q000502:physiology*; D000302:Adrenal Cortex; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D015786:Cytochromes b5 / Q000378:metabolism; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011725:Pyridines; D012333:RNA, Messenger / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D005576:Colforsin; D004004:Dichlororibofuranosylbenzimidazole; D015786:Cytochromes b5; D013254:Steroid 17-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D029404:Activin Receptors; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C093642:SB 203580