Transcriptional activation of nuclear factor (
NF)-kappaB, signal transducers and activators of transcription (STAT) 3, activating
protein (AP)-1 and
CCAAT/enhancer-binding protein (C/EBP) plays an important role in liver regeneration by modulating cell cycle regulators. The regeneration of cirrhotic liver after
hepatectomy is inhibited despite intact expression of
growth factors. To elucidate the mechanism involved, regeneration responses in
growth factor receptors,
transcription factors, and cell cycle regulators after two-thirds
hepatectomy were compared between rats with
thioacetamide-induced cirrhotic and normal liver. The expression of c-met and
epidermal growth factor receptor analyzed by RT-PCR and immunohistochemistry did not differ between the two groups. The activities of C/EBP and
AP-1 evaluated by electrophoretic mobility shift assay were significantly inhibited in the cirrhotic group compared with those in the control group, but not those of
NF-kappaB and STAT3. The expression of cyclin-D1, -E, and -A assessed by Western blot analysis was significantly decreased in the cirrhotic group compared with the control group. The level in p21(Cip1) or p27(Kip1) did not differ between the two groups. The liver regeneration estimated by the rates of [(3)H]
thymidine incorporation into
DNA and staining of
proliferating cell nuclear antigen was significantly lower in the cirrhotic rats than in the controls. In conclusion, downregulation of
cyclin -D1, -E, and -A expression, which may be induced by impaired activities of C/EBP and
AP-1, is responsible for the decreased regenerative capacity of cirrhotic liver after partial
hepatectomy.