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 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.
Schioppa
Tiziana
T
Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy.
Uranchimeg
Badarch
B
Saccani
Alessandra
A
Biswas
Subhra K
SK
Doni
Andrea
A
Rapisarda
Annamaria
A
Bernasconi
Sergio
S
Saccani
Simona
S
Nebuloni
Manuela
M
Vago
Luca
L
Mantovani
Alberto
A
Melillo
Giovanni
G
Sica
Antonio
A
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D010586:Phagocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D017931:DNA Primers; D012333:RNA, Messenger; D019718:Receptors, CXCR4