Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0038002 (
splenomegaly
)
9,873
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The Lyn tyrosine kinase plays essential inhibitory signaling roles within hematopoietic cells by recruiting inhibitory phosphatases such as SH2-domain containing phosphatase-1 (SHP-1), SHP-2, and SH2-domain containing 5'-inositol phosphatase (
SHIP-1
) to the plasma membrane in response to specific stimuli. Lyn-deficient mice display a collection of hematopoietic defects, including autoimmune disease as a result of autoantibody production, and perturbations in myelopoiesis that ultimately lead to
splenomegaly
and myeloid neoplasia. In this study, we demonstrate that loss of Lyn results in a stem/progenitor cell-intrinsic defect leading to an age-dependent increase in myeloid, erythroid, and primitive hematopoietic progenitor numbers that is independent of autoimmune disease. Despite possessing increased numbers of erythroid progenitors, and a more robust expansion of these cells following phenylhydrazine challenge, Lyn-deficient mice are more severely affected by the chemotherapeutic drug 5-fluorouracil, revealing a greater proportion of cycling progenitors. We also show that mice lacking
SHIP-1
have defects in the erythroid and myeloid compartments similar to those in mice lacking Lyn or SHP-1, suggesting an intimate relationship between Lyn, SHP-1, and
SHIP-1
in regulating hematopoiesis.
...
PMID:Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1. 1533 45
SHIP-1
has an important role in controlling immune cell function through its ability to downmodulate PI3K signaling pathways that regulate cell survival and responses to stimulation. Mice deficient in
SHIP-1
display several chronic inflammatory phenotypes including antibody-mediated autoimmune disease, Crohn's disease-like ileitis and a lung disease reminiscent of chronic obstructive pulmonary disease. The ileum and lungs of
SHIP-1
-deficient mice are infiltrated at an early age with abundant myeloid cells and the mice have a limited lifespan primarily thought to be due to the consolidation of lungs with spontaneously activated macrophages. To determine whether the myeloid compartment is the key initiator of inflammatory disease in
SHIP-1
-deficient mice, we examined two independent strains of mice harboring myeloid-restricted deletion of
SHIP-1
. Contrary to expectations, conditional deletion of
SHIP-1
in myeloid cells did not result in consolidating pneumonia or segmental ileitis typical of germline
SHIP-1
deficiency. In addition, other myeloid cell abnormalities characteristic of germline loss of
SHIP-1
, including flagrant
splenomegaly
and enhanced myelopoiesis, were absent in mice lacking
SHIP-1
in myeloid cells. This study indicates that the spontaneous inflammatory disease characteristic of germline
SHIP-1
deficiency is not initiated solely by LysM-positive myeloid cells but requires the simultaneous loss of
SHIP-1
in other hematolymphoid lineages.
...
PMID:SHIP-1 deficiency in the myeloid compartment is insufficient to induce myeloid expansion or chronic inflammation. 2459 98
