1. ¹Department of Pharmacology, University of Michigan Medical School, 1150W. Medical Center Dr., Ann Arbor, MI 48109, USA
2. ²Department of Human Genetics and Program in Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA

Correspondence: AW-M Lee, Department of Pharmacology, The University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA. Tel: 734-647-6004; Fax: 734-647-6202; E-mail: awmlee@umich.edu

Received 19 August 2005; Revised 22 December 2005; Accepted 17 January 2006; Published online 3 March 2006.

Abstract

Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (KI) 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, KI 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 regulation of HKII and support of glycolysis.