Up-regulated Transcriptional Repressors SnoN and Ski Bind Smad Proteins to Antagonize Transforming Growth Factor-β Signals during Liver Regeneration

Abstract

Transforming growth factor-␤ (TGF-␤) functions as an antiproliferative factor for hepatocytes. However, for unexplained reasons, hepatocytes become resistant to TGF-␤ signals and can proliferate despite the presence of TGF-␤ during liver regeneration. TGF-␤ is up-regulated during liver regeneration, although it is not known whether it is active or latent. TGF-␤ activity may be examined by assessing Smad activation, a downstream signaling pathway. Smad pathway activation during liver regeneration induced by partial hepatectomy or CCl 4 injury was examined by assessing the levels of phospho-Smad2 and Smad2-Smad4 complexes. We found that Smad proteins were slightly activated in quiescent liver, but that their activation was further en-

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

“…In addition, after PH, SnoN expression is up-regulated by TGF-␤/Smad2/3-mediated signaling. 34 Therefore, the maintenance of TGF-␤ receptor expression up to 72 hours after PH and the high phospho-Smad2/3 content during this period likely contribute to the increased expression of SnoN in regenerating livers lacking PTP1B. These results are in agreement with the increased SnoN levels and improved liver regeneration in Cav-1 Ϫ/Ϫ mice, as reported recently.…”

“…49 More important, levels of SnoN, an inhibitor of the TGF-␤-Smad signaling pathway, are also increased during the main proliferative phase in regenerating liver. 34 In light of these data, we show that PTP1B deletion concurs with an increase in SnoN expression and cell proliferation in both the in vivo model of liver regeneration and in vitro in cultured hepatocytes. In chronic kidney diseases, HGF abolished TGF-␤ signaling by inducing SnoN in tubular epithelial cells.…”

“…Transforming growth factor ␤ via Smad is the main antiproliferative factor within the liver and, therefore, inhibitors of the TGF-␤-Smad pathway, such as Ski-related novel gene (SnoN) and Ski, are up-regulated during regeneration. 34 Because liver regeneration was increased at late periods after PH in PTP1B Ϫ/Ϫ mice compared with the PTP1B ϩ/ϩ controls (Figure 1), we analyzed the expression of SnoN along this process. Figure 7B shows that increased SnoN levels were detected within 36 to 72 hours after PH in PTP1B ϩ/ϩ mice, decreasing thereafter.…”

Cell cycle regulation and hepatocarcinogenesis

“…However several potential mechanisms have been identified including downregulation of the TGF-β receptors 117 and increased expression of proteins that antagonize TGF-β signals during liver regeneration. 118 When the TGF-β type II receptor was selectively deleted in hepatocytes using the Cre/loxP system, cell cycle progression was accelerated suggesting that TGF-β slows hepatocyte cell cycle progression in the regenerating liver, which is consistent with the data on TGF-β receptor expression in HCC discussed above. 119 These findings taken together are consistent with the notion that at early stages, TGF-β functions as a tumor suppressor through its ability to inhibit hepatocyte proliferation.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…TGF‐β1 levels are raised in the first 2 hours after PHx, and expression levels of downstream Smads, phospho‐Smad2, Smad2, and Smad4 are similarly elevated 95, 113. Concomitant up‐regulation of TGF‐β inhibitory proteins, SnoN and Ski, and a down‐regulation of the TGF‐β receptors, allows hepatocytes to transition from G1 to S phase 114. TBRII‐conditional knockout mice demonstrate accelerated proliferation and an increased liver mass to body weight ratio after PHx 115…”