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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1104-1118
RAPID COMMUNICATION
Erythropoietin Receptor and STAT5-Specific Pathways Promote SKT6
Cell Hemoglobinization
Richard C. Gregory,
Ning Jiang,
Kazuo Todokoro,
Jill Crouse,
Robert E. Pacifici, and
Don M. Wojchowski
From the Department of Biochemistry and Molecular Biology, the Center
for Gene Regulation, the Graduate Program in Genetics, and the
Department of Veterinary Science, The Pennsylvania State Univeristy,
University Park, PA; the Tsukuba Life Science Center, Tsukuba, Ibaraki,
Japan; and Amgen, Inc, Thousand Oaks, CA.
Erythrocyte production in mammals is known to depend on the exposure
of committed progenitor cells to the glycoprotein hormone erythropoietin (Epo). In chimeric mice, gene disruption experiments have demonstrated a critical role for Epo signaling in development beyond the erythroid colony-forming unit (CFU-e) stage. However, whether this might include the possible Epo-specific induction of red
blood cell differentiation events is largely unresolved. To address
this issue, mechanisms of induced globin expression in Epo-responsive
SKT6 cells have been investigated. Chimeric receptors containing an
epidermal growth factor (EGF) receptor extracellular
domain and varied Epo receptor cytoplasmic domains first were expressed
stably at physiological levels in SKT6 cells, and their activities in
mediating induced hemoglobinization were assayed. While activity was
exerted by a full-length chimera (EE483), truncation to remove 7 of 8 carboxyl-terminal tyrosine sites (EE372) markedly enhanced
differentiation signaling. Moreover, mutation of a STAT5 binding site
in this construct (EE372-Y343F) inhibited induced globin expression and
SKT6 cell hemoglobinization, as did the ectopic expression of
dominant-negative forms of STAT5 in parental SKT6 cells. As in normal
CFU-e, SKT6 cells also were shown to express functional receptors for
stem cell factor (SCF). To further define possible
specific requirements for differentiation signaling, effects of SCF on
SKT6 cell hemoglobinization were tested. Interestingly, SCF not only
failed to promote globin expression but inhibited this Epo-induced
event in a dose-dependent, STAT5-independent fashion. Thus, effects of
Epo on globin expression may depend specifically on STAT5-dependent
events, and SCF normally may function to attenuate terminal
differentiation while promoting CFU-e expansion.
© 1998 by The American Society of Hematology.
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