The Hyperresponsiveness of Cells Expressing Truncated Erythropoietin
Receptors Is Contingent on Insulin-Like Growth Factor-1 in Fetal Calf
Serum
Jacqueline E. Damen,
Jana Krosl,
Donna Morrison,
Steven Pelech, and
Gerald Krystal
From the Terry Fox Laboratory, British Columbia Cancer Agency and
Kinetek, Vancouver, British Columbia, Canada.
We demonstrate herein that the well documented hyperresponsiveness
to erythropoietin (Epo) of Ba/F3 cells expressing C-terminal truncated
erythropoietin receptors (EpoRs) is contingent on these cells being in
fetal calf serum (FCS). In the absence of FCS, their Epo-induced
proliferation is far poorer than Ba/F3 cells expressing wild-type (WT)
EpoRs. This hyporesponsiveness in the absence of serum is also seen in
DA-3 cells expressing these truncated EpoRs. In fact, long-term
proliferation studies performed in the absence of serum show that even
at saturating concentrations of Epo, Ba/F3 cells expressing these
truncated receptors die via apoptosis, while cells bearing WT EpoRs do
not, and this programmed cell death correlates with an inability of
Epo-stimulated Ba/F3 cells expressing truncated EpoRs to induce the
tyrosine phosphorylation of MAPK and the activation of
p70S6K. Using neutralizing antibodies to insulin-like
growth factor (IGF)-1, we show that a major non-Epo factor in FCS that
contributes to the hyperresponsive phenotype of Ba/F3 cells expressing
truncated EpoRs is IGF-1. Our results suggest that the
Epo-hypersensitivity of truncated EpoR expressing Ba/F3 cells is due to
the combined effects of these EpoRs not possessing a binding site for
the negative regulator, SHP-1, and the triggering of
proliferation-inducing/apoptosis-inhibiting cascades, lost through EpoR
truncation, by IGF-1.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 425-433
© 1998 by the American Society of Hematology.
