title: Hypoxia-inducible factor-1α induces ErbB4 signaling in the differentiating mammary gland.
abstract: Conditional knock-out of Hif1a in the mouse mammary gland impairs lobuloalveolar differentiation during lactation. Here, we demonstrate that expression of ErbB4 was reduced in the lobulalveoli of mice with mammary gland-specific deletion of Hif1a. Erbb4 was not, however, a direct target gene for transcriptional regulation by HIF-1α in vitro. HIF-1α overexpression or HIF accumulating prolyl hydroxylase inhibitors reduced ErbB4 endocytosis, promoted transcriptional co-regulatory activity of ErbB4, and stimulated ErbB4-induced differentiation of mammary carcinoma cells. Consistently, RNA interference-mediated down-regulation of HIF-1α resulted in reduced ErbB4 protein amount and reduced mammary carcinoma cell differentiation. These findings indicate that HIF-1α is a physiologically relevant regulator of ErbB4 and that ErbB4 is involved in HIF-regulated differentiation of the mammary gland.
authors: From the Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, 20520 Turku, Finland, the Turku Graduate School of Biomedical Sciences, 20520 Turku, Finland.
authors: Ilkka
authors: I
authors: Paatero
authors: the Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors: Tiffany N
authors: TN
authors: Seagroves
authors: From the Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, 20520 Turku, Finland.
authors: Katri
authors: K
authors: Vaparanta
authors: the Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
authors: Wen
authors: W
authors: Han
authors: the Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
authors: Frank E
authors: FE
authors: Jones
authors: the Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 1TN, United Kingdom, and.
authors: Randall S
authors: RS
authors: Johnson
authors: From the Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, 20520 Turku, Finland, the Department of Oncology, Turku University Hospital, 20520 Turku, Finland klaus.elenius@utu.fi.
authors: Klaus
authors: K
authors: Elenius
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004705:Endocytosis; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D011247:Pregnancy; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
keywords: Cell Signaling; Epidermal Growth Factor Receptor (EGFR); ErbB4; Growth Factor; Hypoxia-inducible Factor (HIF); Lactation; Mammary Gland; Receptor Tyrosine Kinase; Signal Transduction