Translational induction of liver-enriched transcriptional inhibitory protein during acute phase response leads to repression of CCAAT/enhancer binding protein alpha mRNA

Lipopolysacharide (LPS) induced acute phase response (APR) in mouse liver l eads to elevation of the low molecular weight CCAAT/Enhancer binding protei n (C/EBP) beta isoform, liver-enriched transcriptional inhibitory protein ( LIP), In this paper, we investigate the pathway for LIP induction during AP R and the role of LIP in regulation of the C/EBP alpha promoter. The 5' reg ion of C/EBP beta mRNA has been shown to be involved in the regulation of L IP translation. Our data demonstrate that binding of cytoplasmic proteins t o the 5' region of C/EBP beta mRNA is altered in response to LPS administra tion, One of the major changes is induced binding of a cytoplasmic protein that is immunologically identical to the previously characterized RNA-bindi ng protein CUGBP1. Induction of CUGBP1 binding activity in liver cytoplasm during APR is accompanied by the elevation of CUGBP1 binding activity on po lysomes, CUGBP1 immunoprecipitated from livers of LPS-treated mice, but not from normal animals, is capable of inducing LIP translation in a cell-free translation system. The ability of CUGBP1 to induce LIP translation during APR depends on phosphorylation of CUGBP1, We show that elevation of LIP du ring APR and after partial hepatectomy leads to increased binding of LIP to the C/EBP consensus site found within the mouse C/EBPa promoter. This bind ing correlates with reduction of C/EBP alpha mRNA levels in both biological situations. Co-transfection experiments showed that full-length C/EBP alph a activates the C/EBP alpha promoter, while LIP blocks this activation. Our data suggest that the dominant negative isoform of C/EBP beta, LIP, down-r egulates the C/EBP alpha promoter in liver and in cultured hepatocytes, Bec ause full-length C/EBP alpha and C/EBP beta proteins regulate liver prolife ration, this function of LIP may be important in liver growth and different iation.