Phosphorylation of rat serine 105 or mouse threonine 217 in C/EBP beta is required for hepatocyte proliferation induced by TGF alpha

We report that TGF alpha induces activation of the p90 ribosomal S kinase ( RSK), which results in the phosphorylation of rat C/EBP beta on Ser-105 and of mouse C/EBP beta on Thr-217 and concomitantly stimulates proliferation in differentiated hepatocytes. Moreover, C/EBP beta(-/-) mouse hepatocytes respond to TGF alpha when wild-type C/EBP beta is reexpressed, whereas they remain refractory to the growth effect of TGF alpha when expressing phosph oacceptor mutants rat C/EBP beta Ala-105 or mouse C/EBP beta Ala-217. In co ntrast, C/EBP beta(-/-) hepatocytes expressing the phosphorylation mimic mu tants, rat C/EBP beta Asp-105 or mouse C/EBP beta Glu-217, exhibited marked proliferation in the absence of TGF alpha. Thus, a site-specific phosphory lation of the transcription factor C/EBP beta is critical for hepatocyte pr oliferation induced by TGF alpha and other stimuli that activate RSK.