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B p50/p65 is regulated in the developing mammary gland and inhibits STAT5-mediated ß-casein gene expression
Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, A-6020 Innsbruck, Austria
1Correspondence: Institute f. Medizinische Chemie und Biochemie, Universität Innsbruck, Fritz Pregl-Str. 3, A-6020 Innsbruck, Austria. E-mail: Wolfgang.Doppler{at}uibk.ac.at osupersub
The NF-
B family of transcription factors regulates diverse cellular
functions such as immune response and cell growth and development, and
has been reported to be constitutively active in a variety of mammary
carcinoma cell lines. However, its role in normal mammary gland
development has not been addressed. In our study, we detected
developmentally regulated NF-B activity in the mammary gland of
mice. During pregnancy, DNA binding activity of NF-B p50/p65
increased until day 16 postcoitum and decreased with the onset of
lactation, most likely due to reduced p50 and p65 protein levels in the
nucleus. Cotransfection experiments performed with 293 cells revealed
an inhibition of the prolactin receptor/JAK2/STAT5 pathway by NF-B.
In HC11 cells, NF-B p50/p65 activity was inversely correlated with
prolactin-induced STAT5 tyrosine phosphorylation, expression of
endogenous ß-casein gene, and of a transfected ß-casein gene
promoter reporter construct. This indicates a negative cross talk
between NF-B and the prolactin receptor/JAK2/STAT5 activation
pathway, which occurs at the level of STAT5 tyrosine phosphorylation.
Our results provide evidence for a role of NF-B in normal mammary
gland development, and indicate its function as a negative regulator of
ß-casein gene expression during pregnancy by interfering with STAT5
tyrosine phosphorylation.—Geymayer, S., Doppler, W. Activation of
NF-B p50/p65 is regulated in the developing mammary gland and
inhibits STAT5-mediated ß-casein gene expression.
Key Words: TNF-
• prolactin • milk protein gene transcription • tyrosine phosphorylation
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