Egr-1 Null Mice Exhibit Impaired Hepatic Regeneration.

Abstract

The liver regenerates itself in response to a wide variety of injuries. The rodent partial hepatectomy model has been a useful tool with which to investigate the signals that regulate this regenerative response. These signals include activation of an immediate-early gene expression program during early liver regeneration which directs growth factor-dependent hepatocellular proliferation and leads to restoration of normal hepatic mass. The early growth response 1 transcription factor (EGR-1), whose expression is known to be regulated in a variety of models of cellular growth and differentiation, has been shown to be induced as part of the immediate early gene expression response during liver regeneration. In the studies reported here the functional significance of EGR-1 expression during liver regeneration was examined by characterizing the hepatic regenerative response to partial hepatectomy in EGR-1 null mice. The results of these studies showed that liver regeneration in EGR-1 null mice is impaired. Although the early signaling events leading up to the first wave of hepatocellular DNA synthesis occurred normally following partial hepatectomy in EGR-1 null mice, subsequent signaling events and cell cycle progression after the first round of DNA synthesis were deranged. This derangement was characterized by increased activation of the p38 mitogen activated protein kinase and inhibition of hepatocellular metaphase-to-anaphase mitotic progression. Together these observations suggest that Egr-1 is an important regulator of hepatocellular mitotic progression through the spindle-assembly checkpoint. In support of this, microarray-based gene expression analysis showed that induction of expression of the cell division cycle 20 gene (CDC20), a key regulator of the mitotic anaphase promoting complex, is significantly reduced in EGR-1 null mice. Taken together these data define a novel functional role for EGR-1 in regulating hepatocellular mitotic progression during liver regeneration.