Abstract
To study the mechanism of beta1-integrin function in vivo, we have generated transgenic mouse expressing a dominant negative mutant of beta1-integrin under the control of mouse mammary tumor virus (MMTV) promoter (MMTV-beta1-cyto). Mammary glands from MMTV-beta1-cyto transgenic females present significant growth defects during pregnancy and lactation and impaired differentiation of secretory epithelial cells at the onset of lactation. We report herein that perturbation of beta1-integrin function in involuting mammary gland induced precocious dedifferentiation of the secretory epithelium, as shown by the premature decrease in beta-casein and whey acidic protein mRNA levels, accompanied by inactivation of STAT5, a transcription factor essential for mammary gland development and up-regulation of nuclear factor-kappaB, a negative regulator of STAT5 signaling. This is the first study demonstrating in vivo that cell-extracellular matrix interactions involving beta1-integrins play an important role in the control of milk gene transcription and in the maintenance of the mammary epithelial cell differentiated state.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology
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CD4 Antigens / genetics
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CD4 Antigens / metabolism
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Cell Differentiation / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / physiology*
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Female
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Genes, Reporter
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Integrin beta1 / genetics
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Integrin beta1 / metabolism*
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Janus Kinase 2
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Lactation / physiology*
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Mammary Glands, Animal / cytology
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Mammary Glands, Animal / physiology*
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Mammary Tumor Virus, Mouse / genetics
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Mice
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Mice, Transgenic
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Milk Proteins / genetics
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NF-kappa B / metabolism
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Pregnancy
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Promoter Regions, Genetic
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / metabolism
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STAT5 Transcription Factor
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Signal Transduction / physiology
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Trans-Activators / genetics
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Trans-Activators / metabolism
Substances
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CD4 Antigens
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DNA-Binding Proteins
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Integrin beta1
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Milk Proteins
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NF-kappa B
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Proto-Oncogene Proteins
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RNA, Messenger
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Recombinant Fusion Proteins
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STAT5 Transcription Factor
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Trans-Activators
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2