INCREASED HEPATIC CELL-PROLIFERATION AND LUNG ABNORMALITIES IN MICE DEFICIENT IN CCAAT ENHANCER BINDING-PROTEIN-ALPHA/

CCAAT/enhancer binding protein alpha (C/EBP alpha) is a transcription factor that has been implicated in the regulation of cell-specific gen e expression mainly in hepatocytes and adipocytes but also in several other terminally differentiated cells. It has been previously demonstr ated that the C/EBP alpha protein is functionally indispensable, as in activation of the C/EBP alpha gene by homologous recombination in mice results in the death of animals homozygous for the mutation shortly a fter birth (Wang, N., Finegold, M. J., Bradley, A., Ou, C. N., Abdelsa yed, S. V., Wilde, M. D., Taylor, L. R., Wilson, D. R., and Darlington , G. J. (1995) Science 269, 1108-1112). Here we show that C/EBP alpha- 1-mice have defects in the control of hepatic growth and lung developm ent. The liver architecture is disturbed, with acinar formation, in a pattern suggestive of either regenerating liver or pseudoglandular hep atocellular carcinoma. Pulmonary histology shows hyperproliferation of type II pneumocytes and disturbed alveolar architecture. At the molec ular level, accumulation of glycogen and lipids in the liver and adipo se tissues is impaired, and the mutant animals are severely hypoglycem ic. Levels of c-myc and c-jun RNA are specifically induced by several fold in the livers of the C/EBP alpha -/- animals, indicating an activ e proliferative stage. Furthermore, immunohistologic detection with an antibody to proliferating cell nuclear antigen/cyclin shows a 5-10 ti mes higher frequency of positively stained hepatocytes in C/EBP alpha -/- liver. These results suggest a critical role for C/EBP alpha in vi vo for the acquisition of terminally differentiated functions in liver including the maintenance of physiologic energy homeostasis.