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STAT3 down-regulates the expression of cyclin D during liver development
Takaaki Matsui1, Taisei Kinoshita, Toshio Hirano
1Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract:
As the expression of cyclin D1 is induced during liver regeneration and also in hepatic tumor cells, cyclin D1 is likely to play an important role in the proliferation and transformation of hepatocytes. However, the role of cyclin D1 in liver development remains unknown. Here we show that the expression of D-type cyclins including cyclin D1, D2, and D3 is down-regulated along with liver development. In addition, oncostatin M (OSM), an interleukin-6 family cytokine, down-regulated the expression of cyclin D1 and D2 in a primary culture of fetal hepatocytes in which OSM induces hepatic differentiation. Ectopic expression of receptor mutants defective in the activation of either STAT3 or SHP-2/Ras indicated that the down-regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP-2/Ras. Consistently, expression of dominant negative STAT3 but not Ras relieved OSM-induced suppression of cyclin D expression. Activation of STAT3 in fetal hepatocytes of transgenic mice expressing the STAT3-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in the suppression of cyclin D1 and D2 expression. These results indicate that STAT3 activation is necessary and sufficient for down-regulation of D1 and D2 cyclins in fetal hepatocytes. Furthermore, STAT3-C, a constitutively active form of STAT3, suppressed transcription of the cyclin D1 promoter in fetal hepatocytes, whereas it activated the transcription in hepatic tumor cells, huH7 and HepG2. Thus, STAT3-mediated down-regulation of cyclin D expression is rather specific to fetal hepatocytes that are undergoing maturation processes including a reduction of their proliferation potential.
Insights
Cyclin D1, D2, and D3 expression decreases during liver development. Oncostatin M signaling, via STAT3 activation, suppresses cyclin D1 and D2 in fetal hepatocytes, indicating a role in maturation.
Area of Science:
- Molecular Biology
- Hepatology
- Cell Cycle Regulation
Background:
- Cyclin D1 is implicated in liver regeneration and tumor proliferation.
- The role of cyclin D1 in normal liver development is not well understood.
- D-type cyclins (D1, D2, D3) are key regulators of cell cycle progression.
Purpose of the Study:
- To investigate the role of cyclin D1 and other D-type cyclins in liver development.
- To elucidate the signaling pathways involved in regulating cyclin D expression during hepatocyte maturation.
Main Methods:
- Analysis of D-type cyclin expression during liver development.
- Primary culture of fetal hepatocytes treated with oncostatin M (OSM).
- Investigation of signaling pathways (STAT3, SHP-2/Ras) using receptor mutants and dominant-negative constructs.
- Studies in transgenic mice with STAT3-estrogen receptor fusion protein.
- Reporter assays using cyclin D1 promoter in fetal hepatocytes and liver tumor cells.
Main Results:
- D-type cyclin expression (D1, D2, D3) is down-regulated during liver development.
- Oncostatin M (OSM) down-regulates cyclin D1 and D2 expression in fetal hepatocytes, promoting differentiation.
- OSM-induced cyclin D down-regulation is mediated by STAT3 activation, not SHP-2/Ras.
- STAT3 activation is both necessary and sufficient for suppressing cyclin D1 and D2 in fetal hepatocytes.
- STAT3 activation suppresses cyclin D1 promoter activity in fetal hepatocytes but activates it in hepatic tumor cells.
Conclusions:
- STAT3 activation plays a critical role in down-regulating cyclin D1 and D2 expression during fetal liver development and maturation.
- The effect of STAT3 on cyclin D expression is context-dependent, suppressing it in differentiating fetal hepatocytes and activating it in tumor cells.
- This suggests STAT3-mediated regulation of cyclin D is specific to hepatocyte maturation and reduced proliferation potential.