Galpha13 induces preproET-1 gene expression via JNK.
The endothelin B receptor (ETBR) has been shown to mediate autoinduction of endothelin-1 (ET-1). We previously reported that the ET(B)R interacts with Galpha13, a member of the heterotrimeric GTP-binding protein family. In the present study, we examined whether Galpha13 induces preproET-1 (ppET-1) gene transcription, which could result in ET-1 autoinduction in a renal epithelial cell line. We generated a reporter gene construct under control of the ppET-1 promoter region. The construct was transiently expressed in COS-7 cells. Transient expression of ETBR increased the promoter activity of ppET-1 following treatment with 100 nmol/l of ET-1. Expression of Galpha13Q226L or Galpha9209L, constitutively active forms of Galpha13 and Galpha9, also activated the ppET-1 promoter. ETBR-stimulated ppET-1 promoter activity was partially diminished by the expression of dominant negative forms of c-Jun N-terminal kinase (JNK1APF) or MAPK/ERK kinase (MEKK97M). Expression of JNK1APF also inhibited Galpha13Q226L-induced ppET-1 promoter activation. These findings indicate that Galpha13 can induce ppET-1 gene expression through a JNK-mediated pathway. Our results also suggest that this Galpha13-coupled signaling pathway may play an important role in a sustained ET-1 autoinduction loop in various pathophysiological conditions.
Third Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Ken
K
Yamakaw
Kenichiro
K
Kitamura
Hiroshi
H
Nonoguchi
Nobuyuki
N
Takasu
R Tyler
RT
Miller
Kimio
K
Tomita
D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000235:genetics*; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology
D004268:DNA-Binding Proteins; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins