Truncation of c-fes via gene targeting results in embryonic lethality and hyperproliferation of hematopoietic cells

被引:14
作者
Hackenmiller, R
Simon, MC [1 ]
机构
[1] Univ Penn, Sch Med, Howard Hughes Med Inst, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA
[3] Univ Chicago, Comm Genet, Chicago, IL 60637 USA
关键词
D O I
10.1006/dbio.2002.0643
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
The c-fes protooncogene encodes a nonreceptor tyrosine kinase (Fes) implicated in cytokine receptor signal transduction, granulocyte survival, and myeloid differentiation. To study the role of c-fes during myelopoiesis, we generated embryonic stem (ES) cells with a targeted disruption of the c-fes locus. Targeted mutagenesis deletes the C-terminal SH2 and tyrosine kinase domains of c-fes (referred to as c-fes(Deltac/Deltac)). We demonstrate that the c-fes(Deltac/Deltac) allele results in a truncated Fes protein that retains the N-terminal oligomerization domain, but lacks both the SH2 and the tyrosine kinase domain. In vitro differentiation of c-fes(Deltac/Deltac) ES cells results in hyperproliferation of an early myeloid cell. Generation of c-fes(Deltac/Deltac) mutant chimeric mice causes lethality by E13.5 with embryos exhibiting pleiotropic defects, the most striking being cardiovascular abnormalities. These results establish that c-fes is an important regulator of myeloid cell proliferation and embryonic development. (C) 2002 Elsevier Science (USA).
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页码:255 / 269
页数:15
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