REGENERATING LIVERS OF OLD RATS CONTAIN HIGH-LEVELS OF C EBP-ALPHA THAT CORRELATE WITH ALTERED EXPRESSION OF CELL-CYCLE ASSOCIATED PROTEINS/

The nuclear transcription factor, CCAAT/enhancer binding protein alpha (C/EBP alpha) is expressed at high levels in the liver and Inhibits g rowth in cultured cells. We have tested the correlation between C/EBP alpha levels, cell cycle proteins and hepatocyte proliferation in old and young animals as an in vivo model system in which the proliferativ e response to partial hepatectomy (PH) has been shown to be reduced an d delayed in old animals. Here we present evidence that the expression of C/EBP alpha in old rats (24 months) differs from its expression in young animals (6-10 months) during liver regeneration. Induction of p roliferating cell nuclear antigen (PCNA), a marker of DNA synthesis, o ccurs at 24 h after PH in young rats but is delayed and reduced in old animals. Induction of the mitotic-specific protein, cdc2 p34, is 3-4- fold less in regenerating liver of old rats than in the liver of young animals, confirming the reduced proliferative response in old animals . In young rats,the normal regenerative response involves a reduction of 3-4-fold in the levels of C/EBP alpha protein at 3-24 h. In old ani mals, C/EBP alpha is not reduced within 24 h after PH, but a decrease of C/EBP alpha protein levels can be detected at 72 h after PH. Induct ion of C/EBP beta, another member of the C/EBP family, is delayed in o ld animals. Changes in the expression of C/EBP proteins are accompanie d by alteration of the CDK inhibitor, p21, which is also decreased in young rats after PH, but in old animals remains unchanged. High levels of p21 protein in older animals correlate with the lack of cdk2 activ ation. We suggest that the failure to reduce the amount of C/EBP alpha and p21 is a critical event in the dysregulation of hepatocyte prolif eration in old animals following PH.