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Autocrine stimulation by erythropoietin (Epo) requires Epo secretion
JL Villeval, MT Mitjavila, I Dusanter-Fourt, F Wendling, P Mayeux and W Vainchenker
INSERM U.362, Institut Gustave Roussy, Villejuif, France.
Erythropoietin (Epo) autocrine stimulation has been implicated in
erythroblastic leukemia. To examine whether this stimulation could occur
intracellularly, we developed Epo autocrine models of stimulation in the
human pluripotent UT-7 cell line. Retroviral expression of Epo totally
abolished the growth factor requirement of UT-7 cells. Autonomous
proliferation was not cell density-dependent and occurred at a unicellular
level, showing a genuine autocrine mode of stimulation. Total blockage of
Epo secretion induced by the endoplasmic reticulum- retention amino acids
Lys-Asp-Glu-Leu (KDEL) signals in 11 lines prevented autonomous
proliferation, whereas a leaky retention system, observed in 3 other lines,
resulted in limited autocrine stimulation without true long-term autonomous
proliferation. Production of Epo, in contrast to KDEL-modified Epo, induced
reductions in Epo binding, Epo receptor (EpoR) mRNA, and phosphorylation
levels similar to those induced by the addition of exogenous Epo to the
parental cell line. In addition, autonomous growth and survival were
inhibited by the addition of Epo-neutralizing antibodies, affording
evidence that autocrine stimulation through EpoR activation takes place on
the cell surface. Finally, phenotypic analysis of the virus-infected clones
indicated that Epo production did not change the differentiative capacities
of UT- 7 cells. All these data show that Epo autocrine stimulation is
dependent on Epo secretion and takes place on the cell surface. From all
analyzed parameters, the effects of Epo autocrine stimulation and those of
exogenously added Epo appear to be identical.
Volume 84,
Issue 8,
pp. 2649-2662,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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