ERK2 but not ERK1 plays a key role in hepatocyte replication

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Abstract
The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 have been implicated in various physiological events, and specific targeting of these MAPKs could affect cell proliferation in many cell types. First, to evaluate the potential specific roles of these two MAPKs, we analyzed the mitogenic response in regenerating liver after partial hepatectomy (PH) and in primary culture of hepatocytes isolated from ERK1-deficient mice. We show that ERK1 knockout and wild-type (wt) cells replicate with the same kinetics after PH in liver, in vivo, and in primary cultures of hepatocytes, in vitro. Indeed, Cyclin D1 and Cdk1 appear to be expressed concomitantly in knockout and wt cells, highlighting that hepatocytes progress in the cell cycle independently of the presence of ERK1. Second, we specifically abolished ERK2 expression by RNA interference in mouse and rat hepatocytes. We investigated whether small interfering RNA (siRNA) targeting ERK2 could specifically inhibit its expression and interfere with the process of replication. In ERK1-deficient hepatocytes, silencing ERK2 expression by RNA interference and ERK2 activation by U0126 clearly demonstrate that DNA replication is regulated by an ERK2-dependent mechanism. Furthermore, in rat wt hepatocytes, whereas ERK2 targeting inhibits late G1 and S phase progression, ERK1 silencing is devoid of any effect on cell proliferation, indicating that ERK1 cannot rescue ERK2 deficiency. Conclusion: Our results emphasize the importance of the MAPK cascade in hepatocyte replication and allow us to conclude that ERK2 is the key form involved in this regulation, in vivo and in vitro. (HEPATOLOGY 2007;45:1035–1045.)