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

PublisherAMER 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

DOIhttps://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.



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