Molecular Basis for the Cell Type–Specific Induction of SnoN Expression by Hepatocyte Growth Factor

Abstract

Hepatocyte growth factor (HGF) is a potent antifibrotic cytokine that antagonizes the TGF-␤1/Smad signaling in diverse types of kidney cells by different mechanisms. HGF is shown to induce Smad co-repressor Sloan-Kettering Institute proto-oncogene-related novel gene, non-Alu-containing (SnoN) expression in proximal tubular epithelial cells (HKC-8) but not in glomerular mesangial cells and interstitial fibroblasts. This study investigated the molecular mechanisms underlying the cell type-specific induction of SnoN by HGF. Treatment of HKC-8 cells with actinomycin D completely abolished HGFmediated SnoN induction, suggesting its dependence on gene transcription. Although HGF activated several signal pathways in HKC-8 cells, blockade of extracellular signal-regulated kinase-1 and -2 (Erk-1/2) activation but not Akt and p38 mitogen-activated protein kinase abolished SnoN induction. HGF rapidly activated both upstream and downstream signaling of Erk-1/2, which led to the activation of the cAMP response element-binding protein (CREB). In the promoter region of human SnoN gene, two cAMP response elements were located in close proximity to Sp1 sites. Chromatin immunoprecipitation assay revealed that activated CREB and Sp1 bound to their cognate cis-acting elements in SnoN promoter in response to HGF stimulation. Ectopic expression of wild-type CREB promoted SnoN expression, whereas dominant negative mutant CREB abrogated SnoN induction by HGF. Likewise, chemical blockade of Sp1 binding abolished HGF-mediated SnoN induction. Furthermore, HGF selectively induced CREB phosphorylation in HKC-8 cells but not in mesangial cells and fibroblasts. In vivo, administration of HGF gene induced renal Erk-1/2 phosphorylation, CREB activation, and SnoN expression in obstructive nephropathy. Collectively, these results suggest that CREB activation, in concert with Sp1, constitutes a molecular switch that confers the cell type-specific induction of SnoN in response to HGF stimulation.

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

“…In chronic kidney diseases, HGF abolished TGF-␤ signaling by inducing SnoN in tubular epithelial cells. 50 Because PTP1B Ϫ/Ϫ hepatocytes are hypersensitive to HGF-induced ERK phosphorylation, this effect might explain the overexpression of SnoN in the liver of PTP1B Ϫ/Ϫ mice before surgery. In addition, after PH, SnoN expression is up-regulated by TGF-␤/Smad2/3-mediated signaling.…”

Impairment of Transforming Growth Factor β Signaling in Caveolin-1-deficient Hepatocytes

“…Ϫ/Ϫ Liver Cells after PH-HGF, a potent inducer of DNA synthesis and cell scatter in cultured hepatocytes, promotes the expression of SnoN (32). In addition to this, the interaction of Cav-1 with c-Met (HGF receptor) has been described (33).…”

MicroRNA-214 Antagonism Protects against Renal Fibrosis

“…Creb1 is a nuclear transcription factor that is ubiquitously expressed and was previously shown specifically in tubular cells to promote skirelated novel gene N (SnoN), which can block the ability of Smads in the nucleus to transactivate gene expression and thus TGF-b signaling. 26 SKI, along with SnoN, is a smad transcriptional corepressor but it blocks Smad 2 phosphorylation rather than Smad 3. 27 This may explain why the levels of p-Smad 2/3 nuclear translocation are unaltered by the loss of miR-214 and suggest that it is mainly p-Smad 3 translocating.…”