Abstract
The HC11 mouse mammary epithelial cell line has proven to be a valuable in vitro model to study the roles of peptide factors and hormones involved in the growth and differentiation of mammary cells. Treatment of HC11 cells with the lactogenic hormones, dexamethasone, insulin, and PRL (DIP), leads to cellular differentiation and production of the milk protein beta-casein. We have analyzed the effects of Neu differentiation factor (NDF)/heregulin, a newly described activating ligand for erbB-2 and other members of the epidermal growth factor (EGF) receptor family, on cell growth and the expression of milk proteins in HC11 cells. In these cells, NDF induces tyrosine phosphorylation of erbB-2 and erbB-3. Both NDF and EGF stimulate HC11 cell proliferation and promote the responsiveness of HC11 cells to lactogenic hormones. NDF induces the expression of a 22-kilodalton milk protein. This protein is up-regulated by other factors, including dexamethasone, EGF, and basic fibroblast growth factor, and is controlled in a manner distinct from that of beta-casein. Like EGF, NDF inhibits the DIP-induced expression of beta-casein at the level of transcription. The inhibition is due to the negative effect of NDF on the activation of mammary gland factor (MGF/Stat5), a member of the Stat family of transcription factors, which is essential for beta-casein gene expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Caseins / biosynthesis
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Caseins / genetics
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cell Line
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DNA Replication / drug effects
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Dexamethasone / pharmacology
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Epidermal Growth Factor / pharmacology
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Epithelium / drug effects
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ErbB Receptors / metabolism
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Female
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Gene Expression Regulation / drug effects
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Glycoproteins / pharmacology*
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Insulin / pharmacology
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Mammary Glands, Animal / drug effects*
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Molecular Sequence Data
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Neuregulins
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Phosphorylation
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Pregnancy
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Prolactin / pharmacology
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Protein Processing, Post-Translational / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-3
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Recombinant Proteins / pharmacology
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Ribosomal Protein S6 Kinases
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Transcription, Genetic / drug effects
Substances
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Caseins
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Glycoproteins
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Insulin
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Neuregulins
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Proto-Oncogene Proteins
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Recombinant Proteins
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Epidermal Growth Factor
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Dexamethasone
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Prolactin
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ErbB Receptors
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Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Receptor, ErbB-3
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases