Regulation of colony-stimulating factor 1-induced proliferation by
heterotrimeric Gi2 proteins
I Corre and S Hermouet
Laboratoire d'Oncogenese Immunohematologique, Institut de Biologie des
Hopitaux de Nantes, France.
Receptors for hematopoietic cytokines possess intrinsic tyrosine- kinases
or are associated with tyrosine-kinases; interactions between metabolic
pathways activated by tyrosine-kinases and heterotrimeric G proteins are
suspected, but not yet proven. To investigate whether alteration of G
protein function affects signal transduction of hematopoietic cytokines, we
expressed mutant Gi2 proteins in BAC 1.2F5 cells, a murine macrophage cell
line that is dependent from monocyte- macrophage colony-stimulating factor
(CSF 1) for its proliferation. Mutations made in alpha subunits
constitutively activate (alpha i2- Q205L) or inactivate (alpha i2-G204A)
Gi2 heterotrimers. We show that expression of alpha i2-Q205L in BAC 1.2F5
cells does not induce independence from CSF 1, but reduces the cells'
requirement in CSF 1, shortens the length of the G1 phase and the cell
doubling time in response to CSF 1, and protects cells from death by
apoptosis induced by CSF 1 withdrawal, exposure to H2O2 or heat shock, but
not mitoxantrone. More importantly, expression of alpha i2-G204A, a
dominant negative mutant, inhibits BAC 1.2F5 cell proliferation in response
to CSF 1, increases the length of the G1 phase and the cell doubling time,
and accelerates apoptotic cell death after withdrawal of CSF 1, exposure to
H2O2 or heat shock. We conclude that the metabolic pathways regulated by
Gi2 proteins and CSF 1 tyrosine-kinase receptors converge on a common
effector necessary for the regulation of macrophage survival and
proliferation.
Volume 86,
Issue 5,
pp. 1776-1783,
09/01/1995
Copyright © 1995 by The American Society of Hematology
