Hypoxia-inducible Factor-1α Induces ErbB4 Signaling in the Differentiating Mammary Gland
: Ilkka Paatero, Tiffany N. Seagroves, Katri Vaparanta, Wen Han, Frank E. Jones, Randall S. Johnson, Klaus Elenius
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
: 2014
: Journal of Biological Chemistry
: JOURNAL OF BIOLOGICAL CHEMISTRY
: J BIOL CHEM
: 289
: 32
: 22459
: 22469
: 11
: 0021-9258
: 1083-351X
DOI: https://doi.org/10.1074/jbc.M113.533497
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-1 alpha in vitro. HIF-1 alpha 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-1 alpha resulted in reduced ErbB4 protein amount and reduced mammary carcinoma cell differentiation. These findings indicate that HIF-1 alpha is a physiologically relevant regulator of ErbB4 and that ErbB4 is involved in HIF-regulated differentiation of the mammary gland.