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

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-1α is a transcriptional activator of DDX3 in bre...

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Bibliographic Details
Published in:PloS one 2011-03, Vol.6 (3), p.e17563
Main Authors: Botlagunta, Mahendran, Krishnamachary, Balaji, Vesuna, Farhad, Winnard, Jr, Paul T, Bol, Guus M, Patel, Arvind H, Raman, Venu
Format: Article
Language:English
Subjects:
Aberration
Animals
Apoptosis
Base Sequence
Binding
Binding sites
Biology
Breast - pathology
Breast cancer
Cancer
Cancer therapies
Cell Hypoxia - drug effects
Cell Line, Tumor
Cell survival
Chromatin
Chromatin Immunoprecipitation
Cobalt - pharmacology
DEAD box protein
DEAD-box RNA Helicases - genetics
DEAD-box RNA Helicases - metabolism
Epidermal growth factor
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Female
Gangrene
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Genes
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Immunoprecipitation
Invasiveness
Kinases
Luciferase
Medicine
Metabolism
Metastasis
Mice
Molecular Sequence Data
Mutation
Protein Binding - drug effects
Protein Stability - drug effects
Protein Transport - drug effects
Radiology
Regulatory sequences
Respiration
Response Elements - genetics
Rodents
siRNA
Stem cells
Studies
Transcription activation
Transcription factors
Tumors
Xenograft Model Antitumor Assays
Xenografts
Xenotransplantation
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Summary: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-1α 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-1α 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0017563