Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells

Botlagunta, M., Krishnamachary, B., Vesuna, F., Winnard, P.T., Bol, G.M., Patel, A.H. and Ramanathan, V. (2011) Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells. PLoS ONE, 6(3), e17563. (doi: 10.1371/journal.pone.0017563) (PMID:21448281) (PMCID:PMC3063174)

Abstract

DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1 alpha is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1 alpha and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Patel, Professor Arvind
• Authors: Botlagunta, M., Krishnamachary, B., Vesuna, F., Winnard, P.T., Bol, G.M., Patel, A.H., and Ramanathan, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Published Online: 23 March 2011
• Copyright Holders: Copyright © 2011 The Authors
• First Published: First published in PLoS ONE 6(3):e17563
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher