Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Cell Death and Differentiation
A W Lee, D J States

Abstract

Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DeltaKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DeltaKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x(L) expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regula...Continue Reading

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Citations

Apr 21, 2009·Journal of Bioenergetics and Biomembranes·Shigeki MiyamotoJoan Heller Brown
Nov 3, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·Shungo HiroyasuNicholas E S Sibinga
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Jan 17, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yi ZhouWentian Yang
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Mar 21, 2019·Animal Models and Experimental Medicine·Wei DongDan Lu
Mar 7, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Elisabetta RovidaPersio Dello Sbarba
Jul 1, 2017·The Journal of Clinical Investigation·Kelli Pa MacDonaldGeoffrey R Hill

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