| First Author | Chen Y | Year | 2023 |
| Journal | Am J Pathol | Volume | 193 |
| Issue | 9 | Pages | 1143-1155 |
| PubMed ID | 37263346 | Mgi Jnum | J:339672 |
| Mgi Id | MGI:7523713 | Doi | 10.1016/j.ajpath.2023.05.007 |
| Citation | Chen Y, et al. (2023) Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-beta1-Induced Apoptosis in Hepatocytes. Am J Pathol 193(9):1143-1155 |
| abstractText | Dysregulation of hepatocyte apoptosis is associated with several types of chronic liver diseases. Transforming growth factor-beta1 (TGF-beta1) is a well-known pro-apoptotic factor in the liver, which constitutes a receptor complex composed of TGF-beta receptor I and II, along with transcription factor Smad proteins. As a member of the forkhead box O (Foxo) class of transcription factors, Foxo1 is a predominant regulator of hepatic glucose production and apoptosis. This study investigated the potential relationship between TGF-beta1 signaling and Foxo1 in control of apoptosis in hepatocytes. TGF-beta1 induced hepatocyte apoptosis in a Foxo1-dependent manner in hepatocytes isolated from both wild-type and liver-specific Foxo1 knockout mice. TGF-beta1 activated protein kinase A through TGF-beta receptor I-Smad3, followed by phosphorylation of Foxo1 at Ser273 in promotion of apoptosis in hepatocytes. Moreover, Smad3 overexpression in the liver of mice promoted the levels of phosphorylated Foxo1-S273, total Foxo1, and a Foxo1-target pro-apoptotic gene Bim, which eventually resulted in hepatocyte apoptosis. The study further demonstrated a crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-beta1 by using hepatocytes isolated from Foxo1-S273A/A knock-in mice, in which the phosphorylation of Foxo1-S273 was disrupted. Taken together, this study established a novel role of TGF-beta1-->protein kinase A-->Foxo1 signaling cascades in control of hepatocyte survival. |
