Regulation of the chemokine receptor CXCR4 by hypoxia

Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemo...

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Published inThe Journal of experimental medicine Vol. 198; no. 9; pp. 1391 - 1402
Main Authors Schioppa, Tiziana, Uranchimeg, Badarch, Saccani, Alessandra, Biswas, Subhra K, Doni, Andrea, Rapisarda, Annamaria, Bernasconi, Sergio, Saccani, Simona, Nebuloni, Manuela, Vago, Luca, Mantovani, Alberto, Melillo, Giovanni, Sica, Antonio
Format Journal Article
LanguageEnglish
Published United States The Rockefeller University Press 03.11.2003
Subjects
Animals
Base Sequence
Cell Hypoxia
Cells, Cultured
CXCL12 protein
CXCR4 protein
DNA Primers
Endothelium, Vascular - cytology
Endothelium, Vascular - metabolism
Humans
Mice
Phagocytes - metabolism
Receptors, CXCR4 - genetics
Receptors, CXCR4 - metabolism
Receptors, CXCR4 - physiology
RNA, Messenger - genetics
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Summary:Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to stromal-derived factor 1 (CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor, CXC receptor 4 (CXCR4), in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by Hyp is dependent on both activation of the Hyp-inducible factor 1 alpha and transcript stabilization. In a relay multistep navigation process, the Hyp-Hyp-inducible factor 1 alpha-CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.
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Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; DFX, desferrioxamine; HIF-1, Hyp-inducible factor 1; HRE, Hyp responsive element; HUVEC, human umbilical vein endothelial cell; Hyp, hypoxia; MDM, monocyte-derived macrophage; MEF, mouse embryonic fibroblast; Norm, normoxia; pVHL, von Hippel–Lindau tumor suppressor protein; SDF-1, stromal-derived factor 1; TAM, tumor-associated macrophage; VEGF, vascular endothelial growth factor; VHL, von Hippel–Lindau tumor suppressor protein.
Address correspondence to Antonio Sica, Istituto di Ricerche Farmacologiche “Mario Negri,” via Eritrea 62, 20157 Milan, Italy. Phone: 39-02-2390-14530; Fax: 39-02-2332-00231; email: sica@marionegri.it; or Giovanni Melillo, Development Therapeutic Program, Tumor Hypoxia Laboratory, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21701. Phone: (301) 846-5050; Fax: (301) 846-6081; email: melillo@dtpax2.ncifcrf.gov
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20030267