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The Liver-Enriched Inhibitory Protein Isoform of CCAAT/Enhancer-Binding Protein ß, But Not Nuclear Factor-B, Mediates the Transcriptional Inhibition of ß-Casein by Tumor Necrosis Factor-

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

Address all correspondence and requests for reprints to: Margot M. Ip, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263. E-mail: margot.ip{at}roswellpark.org.

TNF- is a physiological regulator of mammary gland development that stimulates the growth of both normal and malignant mammary epithelial cells in primary culture and inhibits functional differentiation. To understand how TNF exerts its effects, the current study examined the mechanism by which TNF down-regulates expression of the ß-casein and whey acidic protein (WAP) genes. TNF treatment markedly decreased activity of the ß-casein and WAP promoters in transiently transfected HC11 mammary epithelial cells. Overexpression of the nuclear factor-B (NFB) p50 and/or p65 proteins increased the transcriptional activity of the ß-casein and WAP promoters in HC11 cells, suggesting that the inhibitory effect of TNF on transcription of these genes is not mediated by NFB. This was further confirmed in experiments in which an NFB super-repressor was overexpressed, and by deletion of an NFB binding site in the ß-casein promoter. In contrast, we found that TNF induced both nuclear expression and the DNA-binding activity of liver-enriched inhibitory protein (LIP) isoform of CCAAT/enhancer-binding protein ß. Moreover, cotransfection of LIP and ß-casein expression vectors showed that LIP suppressed the transcriptional activity of the ß-casein promoter. Together, these results suggest that LIP plays a critical role in mediating TNF-induced down-regulation of the ß-casein gene.

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