Requirement for phosphatidylinositol 3′-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor

Christian T Minshall, Sean Arkins, Gregory G. Freund, Keith W. Kelley

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Hemopoietic growth factors promote survival of progenitor cells by preventing their apoptotic death. Recently, phosphatidyl-inositol 3′-kinase (PI 3-kinase) has been shown to be integral in the pathway by which insulin and nerve growth factor prevent apoptosis. In this work, we show that IL-3-dependent FDCP-1/Mac-1 murine hemopoietic progenitors express receptors for another growth factor, insulin-like growth factor-I (IGF-I), and that both IL-3 and IGF-I stimulate PI 3-kinase activity. We then demonstrate that IGF-I shares with IL-3 the properties of significantly promoting proliferation and enhancing survival of myeloid progenitor cells at concentrations as low as 3 ng/ml. IL-3 and IGF-I efficiently promote cell survival in the presence of inhibitors of either RNA synthesis (actinomycin D) or mitosis (mitomycin C), suggesting that both ligands promote survival by a process that is largely independent of RNA synthesis. To determine whether PI 3-kinase mediates IL-3- and IGF-I-induced inhibition of apoptosis, FDCP-1/Mac-1 cells were incubated with the PI 3-kinase inhibitor, wortmannin. While wortmannin inhibited both basal and IGF-I- and IL-3-induced PI 3-kinase enzyme activity, it did not affect the ability of IL-3 to protect FDCP-1/Mac-1 cells from apoptosis, even though it abrogated the IGF-I-induced inhibition of apoptosis. These data demonstrate that even though activation of PI 3-kinase is a pleiotropic feature of both IL-3 and IGF-I receptors in myeloid progenitors, prevention of apoptosis by IL-3 but not IGF-I is independent of PI 3-kinase. Survival of hemopoietic progenitors is therefore maintained by at least two different intracellular signaling pathways, one requiring PI 3-kinase and one that does not.

Original languageEnglish (US)
Pages (from-to)939-947
Number of pages9
JournalJournal of Immunology
Volume156
Issue number3
StatePublished - Feb 1 1996

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Phosphatidylinositol 3-Kinase
Interleukin-3
Phosphatidylinositols
Insulin-Like Growth Factor I
Phosphotransferases
Apoptosis
Nucleic Acid Synthesis Inhibitors
Myeloid Progenitor Cells
IGF Type 1 Receptor
Growth Factor Receptors
Dactinomycin
Mitomycin
Nerve Growth Factor
Mitosis
Cell Survival
Intercellular Signaling Peptides and Proteins
Stem Cells
RNA
Insulin
Ligands

ASJC Scopus subject areas

  • Immunology

Cite this

Requirement for phosphatidylinositol 3′-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor. / Minshall, Christian T; Arkins, Sean; Freund, Gregory G.; Kelley, Keith W.

In: Journal of Immunology, Vol. 156, No. 3, 01.02.1996, p. 939-947.

Research output: Contribution to journalArticle

Minshall, Christian T ; Arkins, Sean ; Freund, Gregory G. ; Kelley, Keith W. / Requirement for phosphatidylinositol 3′-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor. In: Journal of Immunology. 1996 ; Vol. 156, No. 3. pp. 939-947.
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