Activation of NF-kappaB p50/p65 is regulated in the developing mammary gland and inhibits STAT5-mediated beta-casein gene expression.
The NF-kappaB 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-kappaB activity in the mammary gland of mice. During pregnancy, DNA binding activity of NF-kappaB 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-kappaB. In HC11 cells, NF-kappaB p50/p65 activity was inversely correlated with prolactin-induced STAT5 tyrosine phosphorylation, expression of endogenous beta-casein gene, and of a transfected beta-casein gene promoter reporter construct. This indicates a negative cross talk between NF-kappaB 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-kappaB in normal mammary gland development, and indicate its function as a negative regulator of beta-casein gene expression during pregnancy by interfering with STAT5 tyrosine phosphorylation.
Geymayer
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Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, A-6020 Innsbruck, Austria.
Doppler
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D000818:Animals; D002364:Caseins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053614:Janus Kinase 2; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000187:drug effects; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000378:metabolism; D050799:STAT5 Transcription Factor; D012717:Sesquiterpenes / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002364:Caseins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D012717:Sesquiterpenes; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine; C002669:parthenolide; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2