Activation of NF-kappa B p50/p65 is regulated in the developing mammary gland and inhibits STAT5-mediated beta-casein gene expression

The NF-kappa B family of transcription factors regulates diverse cellular f unctions such as immune response and cell growth and development, and has b een reported to be constitutively active in a variety of mammary carcinoma cell lines. However, its role in normal mammary gland development has not b een addressed. In our study, we detected developmentally regulated NF-kappa B activity in the mammary gland of mice. During pregnancy, DNA binding act ivity of NF-kappa B p50/p65 increased until day 16 postcoitum and decreased with the onset of lactation, most likely due to reduced p50 and p65 protei n levels in the nucleus. Cotransfection experiments performed with 293 cell s revealed an inhibition of the prolactin receptor/JAK2/STAT5 pathway by NF -kappa B. In HC11 cells, NF-kappa B p50/p65 activity was inversely correlat ed with prolactin-induced STAT5 tyrosine phosphorylation, expression of end ogenous beta-casein gene, and of a transfected beta-casein gene promoter re porter construct. This indicates a negative cross talk between NF-kappa B a nd the prolactin receptor/JAK2/STAT5 activation pathway, which occurs at th e level of STAT5 tyrosine phosphorylation. Our results provide evidence for a role of NF-kappa B in normal mammary gland development, and indicate its function as a negative regulator of beta-casein gene expression during pre gnancy by interfering with STATS tyrosine phosphorylation.-Geymayer, S., Do ppler, W. Activation of NF-kappa B p50/p65 is regulated in the developing m ammary gland and inhibits STATS-mediated beta-casein gene expression.