Enhanced Endotoxin Sensitivity in Fps/Fes-Null Mice with Minimal Defects in Hematopoietic Homeostasis

Zirngibl, Ralph A; Senis, Yotis A.; Greer, Peter A.

doi:10.1128/mcb.22.8.2472-2486.2002

Cited by 55 publications

(83 citation statements)

References 96 publications

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“…Fes Ϫ/Ϫ macrophages exhibited defects in cell adhesion and GM-CSF signaling, pointing to incomplete maturation of their myeloid compartment. However, targeting of the Fes locus using a different strategy did not reveal alterations in the macrophage or granulocyte populations (43). This low penetrance of the Fes Ϫ/Ϫ phenotype may be a result of functional redundancy.…”

Section: Discussionmentioning

confidence: 92%

Fes Tyrosine Kinase Promotes Survival and Terminal Granulocyte Differentiation of Factor-dependent Myeloid Progenitors (32D) and Activates Lineage-specific Transcription Factors

Kim

Ogata

Feldman

2003

Journal of Biological Chemistry

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The c-fps/fes proto-oncogene encodes a 92-kDa protein-tyrosine kinase that is involved in myeloid cell development and function. We have recently shown that expression of an activated allele of Fes (Fes act ) in monocyte precursors resulted in their differentiation into functional macrophages through the activation of lineage-specific transcription factors. We now report that this kinase also plays a role in the survival and terminal differentiation of granulocyte progenitors. The expression of Fes act in factor-dependent 32D cells prevented their apoptotic death after interleukin-3 removal, but Fes act -expressing cells remained factor-dependent for proliferation. Removal of interleukin-3 from the Fes actexpressing cells was followed by granulocytic differentiation in the absence of granulocyte colony-stimulating factor within 4 -8 days. The differentiated cells had distinctive granulocyte morphology and there was up-regulation of CD11b, Gr-1, and late differentiation markers such as lactoferrin, suggesting that this kinase induced terminal granulocytic differentiation. Concomitantly, Fes act down-regulated the macrophage marker F4/80, suggesting that the biological activity of Fes was coordinated in a lineage-specific manner. Further analysis showed that Fes act caused activation of CCAAT/enhancer-binding protein-␣ and STAT3, two transcription factors that are involved in granulocyte differentiation. Our results provide evidence that Fes may be a key component of the granulocyte differentiation machinery, and suggest a potential mechanism by which this kinase may regulate granulocyte-specific gene expression.

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Section: Discussionmentioning

confidence: 92%

Fes Tyrosine Kinase Promotes Survival and Terminal Granulocyte Differentiation of Factor-dependent Myeloid Progenitors (32D) and Activates Lineage-specific Transcription Factors

Kim

Ogata

Feldman

2003

Journal of Biological Chemistry

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“…Generation and genotyping of in-bred SVJ/129-CD1 hybrid lines harboring targeted null ( fps À/À ), targeted catalytically inactive ( fps KR/KR ), or transgenic ( fps Tg ) fps alleles in a targeted fps-null genetic background ( fps À/À fps Tg ) have been reported previously (6)(7)(8). Generation of in-bred transgenic mice with mouse mammary tumor virus-long terminal repeat-directed, mammary epithelial-specific expression of polyoma virus middle T antigen (PyVmT) has also been described (9).…”

Section: Methodsmentioning

confidence: 99%

An Identity Crisis for fps/fes: Oncogene or Tumor Suppressor?

et al. 2005

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Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/ Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells. (Cancer Res 2005; 65(9): 3518-22)

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“…Other possible c-Fes interactions are summarized in literature (Ferrari et al, 1995;Smithgall et al, 1998;Greer, 2002). Gene targeting experiments in mice have demonstrated that myelopoiesis is not substantially affected by the lack of c-Fes activity or c-Fes (Hackenmiller et al, 2000;Zirngibl et al, 2002). On the other hand, the Hackenmiller group has recently shown, in a further work, that truncation of c-Fes via gene targeting results in embryonic lethality and hyperproliferation of hematopoietic cells (Hackenmiller and Simon, 2002).…”

Section: Introductionmentioning

confidence: 99%

Requirement of the coiled-coil domains of p92c-Fes for nuclear localization in myeloid cells upon induction of differentiation

et al. 2003

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The nonreceptor tyrosine kinase Fes is implicated in myeloid cells differentiation. It has been observed that its localization can be cytoplasmic, perinuclear, or nuclear. To further characterize this point, we studied Fes subcellular localization in myeloid cell lines (HL60 and K562) and in COS1 cells. Fes was observed in both the nucleus and the cytoplasm of HL60, K562 cells overexpressing Fes and only in the cytoplasm of COS1 cells, suggesting that nuclear localization is cell context dependent. Moreover, in myeloid cells, the treatment with differentiation-inducing agents such as retinoic acid, phorbol esters and vitamin D, is followed by an increase of the oligomeric form of Fes in the nucleus. In fact, oligomerization seems to be necessary for translocation to occur, since Fes mutants missing the coiled-coil domains are not able to form oligomers and fail to localize in the nucleus. The active form of Fes is tyrosine phosphorylated; however, phosphorylation is not required for Fes to localize in the nucleus, since tyrosine kinase inhibitors do not block the translocation process.

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Enhanced Endotoxin Sensitivity in Fps/Fes-Null Mice with Minimal Defects in Hematopoietic Homeostasis

Cited by 55 publications

References 96 publications

Fes Tyrosine Kinase Promotes Survival and Terminal Granulocyte Differentiation of Factor-dependent Myeloid Progenitors (32D) and Activates Lineage-specific Transcription Factors

Fes Tyrosine Kinase Promotes Survival and Terminal Granulocyte Differentiation of Factor-dependent Myeloid Progenitors (32D) and Activates Lineage-specific Transcription Factors

An Identity Crisis for fps/fes: Oncogene or Tumor Suppressor?

Requirement of the coiled-coil domains of p92c-Fes for nuclear localization in myeloid cells upon induction of differentiation

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