These authors contributed equally to this work.
Transcription factors ETF, E2F, and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes†
Article first published online: 26 OCT 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 52, Issue 6, pages 2127–2136, December 2010
How to Cite
Zellmer, S., Schmidt-Heck, W., Godoy, P., Weng, H., Meyer, C., Lehmann, T., Sparna, T., Schormann, W., Hammad, S., Kreutz, C., Timmer, J., von Weizsäcker, F., Thürmann, P. A., Merfort, I., Guthke, R., Dooley, S., Hengstler, J. G. and Gebhardt, R. (2010), Transcription factors ETF, E2F, and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes. Hepatology, 52: 2127–2136. doi: 10.1002/hep.23930
Potential conflict of interest: Nothing to report.
- Issue published online: 23 NOV 2010
- Article first published online: 26 OCT 2010
- Accepted manuscript online: 20 AUG 2010 12:00AM EST
- Manuscript Accepted: 10 AUG 2010
- Manuscript Received: 5 MAR 2010
- the German Federal Ministry for Education and Research (BMBF) within the program “Systems of Life – Systems Biology”
- Excellence Iniative of the German Federal and state Governments (EXC 294)
The cellular basis of liver regeneration has been intensely investigated for many years. However, the mechanisms initiating hepatocyte “plasticity” and priming for proliferation are not yet fully clear. We investigated alterations in gene expression patterns during the first 72 hours of C57BL/6N mouse hepatocyte culture on collagen monolayers (CM), which display a high basal frequency of proliferation in the absence of cytokines. Although many metabolic genes were down-regulated, genes related to mitogen-activated protein kinase (MAPK) signaling and cell cycle were up-regulated. The latter genes showed an overrepresentation of transcription factor binding sites (TFBS) for ETF (TEA domain family member 2), E2F1 (E2F transcription factor 1), and SP-1 (Sp1 transcription factor) (P < 0.001), all depending on MAPK signaling. Time-dependent increase of ERK1/2 phosphorylation occurred during the first 48 hours (and beyond) in the absence of cytokines, accompanied by an enhanced bromodeoxyuridine labeling index of 20%. The MEK inhibitor PD98059 blunted these effects indicating MAPK signaling as major trigger for this cytokine-independent proliferative response. In line with these in vitro findings, liver tissue of mice challenged with CCl4 displayed hepatocytes with intense p-ERK1/2 staining and nuclear SP-1 and E2F1 expression. Furthermore, differentially expressed genes in mice after partial hepatectomy contained overrepresented TFBS for ETF, E2F1, and SP-1 and displayed increased expression of E2F1. Conclusion: Cultivation of murine hepatocytes on CM primes cells for proliferation through cytokine-independent activation of MAPK signaling. The transcription factors ETF, E2F1, and SP-1 seem to play a pronounced role in mediating proliferation-dependent differential gene expression. Similar events, but on a shorter time-scale, occur very early after liver damage in vivo. (HEPATOLOGY 2010;.)