Nuclear factor 1-C2 contributes to the tissue-specific activation of a milk protein gene in the differentiating mammary gland.
Members of the nuclear factor 1 (NF1) transcription factor family have been postulated to be involved in the regulation of milk genes. In this work we have been able to identify the splice variant NF1-C2 as an important member of a tissue-specific activating complex that regulates the milk gene encoding carboxyl ester lipase (CEL). Mutation of the NF1-binding site in the CEL gene promoter results in a drastic reduction of the gene expression to about 15% in mammary epithelial cells. Furthermore, we demonstrate that the NF1-C2 protein interacts with a higher affinity to the NF1-binding site in the CEL gene promoter than other NF1 family members do and that NF1-C2 in the mouse mammary gland is a phosphorylated protein. During development of the mouse mammary gland, binding of NF1-C2 to the CEL gene promoter is induced at midpregnancy, in correlation with the induction of CEL gene expression. The fact that the NF1-C2 involving complex remains throughout the lactation period and decreases during the weaning period, when the CEL gene is down-regulated, supports its importance in the regulation of CEL gene expression. To our knowledge, this is the first report identifying a specific, endogenously expressed NF1 isoform to be involved in the tissue-specific activation of a gene.
Kannius-Janson
Marie
M
Department of CMB/Molecular Biology, Box 462, S-405 30 Göteborg, Sweden. Marie.Kannius@molbio.gu.se
Johansson
Eva M
EM
Bjursell
Gunnar
G
Nilsson
Jeanette
J
D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000254:growth & development*; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008894:Milk Proteins / Q000235:genetics*; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D051381:Rats; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase