Immediate early genes and p21 regulation in liver of rats with acute hepatic failure.
It has been observed that liver regeneration in acute hepatic failure (AHF) is suppressed [Eguchi et al. Hepatology 1996;24(6):1452-9]. The molecular mechanism regulating this inhibition is not known. We previously reported that in AHF rats, hepatocyte proliferation was significantly impaired with elevation in serum IL-6, TGF-beta1, and HGF [Kamohara et al. Biochem Biophys Res Commun 2000;273(1):129-35]. Following either 70% partial hepatectomy (PH) or liver injury, quiescent mature hepatocytes are "primed" to re-enter the cell cycle. The process of "priming" appears to be triggered by extracellular cytokines (IL-6 and TNF-alpha) and is characterized by expression of immediate early genes. Under the stimulation of growth factors such as HGF, "primed" hepatocytes exit the G1 phase of the cell cycle. G1-associated cyclins and their inhibitors play a pivotal role in G1/S cell cycle transition. Here, we demonstrate that immediate early gene (i.e. c-myc, c-fos) expression and AP-1 activity are preserved in AHF rat livers despite absence of hepatocyte proliferation. In contrast, p21 mRNA and protein are both over-expressed in AHF livers compared to livers from rats undergoing PH; this elevation leads to inhibition in Cdk2 activity, resulting in G1 cell cycle arrest and inhibition of regeneration.
Hui
Thomas T
TT
Liver Support Research Laboratory, Department of Surgery, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.
Mizuguchi
Toru
T
Sugiyama
Nozomu
N
Avital
Itzhak
I
Rozga
Jacek
J
Demetriou
Achilles A
AA
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D017781:Genes, Immediate-Early / Q000235:genetics*; D016762:Genes, fos / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D006498:Hepatectomy / Q000379:methods; D015850:Interleukin-6 / Q000097:blood; D017114:Liver Failure, Acute / Q000235:genetics* / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics* / Q000502:physiology; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood; D053773:Transforming Growth Factor beta1; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
D019927:Cyclin E; D015850:Interleukin-6; C508962:Tgfb1 protein, rat; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020741:rho GTP-Binding Proteins