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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3804-3811
RED CELLS
A naturally occurring point substitution in Cdc25A,
and not Fv2/Stk, is associated with altered cell-cycle
status of early erythroid progenitor cells
Edward Melkun,
Mylisa Pilione, and
Robert F. Paulson
From the Department of Veterinary Science, The
Schreyer's Honors College, and the Graduate Program in Biochemistry,
Microbiology and Molecular Biology, Pennsylvania State University,
University Park.
The Friend virus susceptibility gene 2 (Fv2) controls
the polyclonal expansion of infected cells that occurs early during Friend erythroleukemia virus infection. Fv2 has recently
been shown to encode a truncated form of the Stk receptor
tyrosine kinase (Sf-Stk). This observation, coupled with earlier work, suggested that Sf-Stk drives the expansion of infected cells by forming
a complex with the Friend virus envelope glycoprotein, gp55, and the
erythropoietin receptor. Fv2 has also been implicated in
the control of cell cycling in early erythroid progenitors (erythroid
blast-forming units [BFU-Es]). Mouse strains that are homozygous for
the resistant allele of Fv2 (Fv2rr) have few
actively cycling BFU-Es. In this report, we demonstrate that the
control of BFU-E cycling is encoded by a gene linked to, but distinct
from, Fv2, and suggest that this gene is the dual-specific
protein phosphatase Cdc25A, which regulates the G1- to S-phase
transition of the cell cycle. We show that a naturally occurring allele
of Cdc25A, which increases Cdc25A phosphatase activity and promotes
cell-cycle progression, segregates in mouse strains that exhibit high
levels of BFU-E cell cycling. In wild-type mice, this allele of Cdc25A
does not overtly affect erythropoiesis; however, when this allele is
combined with a mutation of the Kit receptor
(KitWV), the anemia of the mice is enhanced.
Furthermore, overexpression of Cdc25A in bone marrow cells causes a
defect in the BFU-E colony formation. These results suggest that proper
regulation of the cell cycle through Cdc25A is required for normal erythropoiesis.
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