A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells.
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 (Fv2(rr)) 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 (Kit(WV)), 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.
Melkun
Edward
E
Department of Veterinary Science, The Schreyer's Honors College, and the Graduate Program in Biochemistry, Microbiology and Molecular Biology, Pennsylvania State University, University Park 16802, USA.
Pilione
Mylisa
M
Paulson
Robert F
RF
D000595:Amino Acid Sequence; D000740:Anemia / Q000201:enzymology / Q000235:genetics; D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000201:enzymology; D004920:Erythropoiesis / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017354:Point Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D011956:Receptors, Cell Surface; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases