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: EC:3.1.4.3 (
phospholipase C
)
18,461
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The
FOP
-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of
FOP
to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of
FOP
-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing
FOP
-FGFR1. The survival function of
FOP
-FGFR1 is abrogated by mutation of the
phospholipase C
gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in
FOP
-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that
FOP
-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that
FOP
-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition,
FOP
-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by
FOP
-FGFR1. Finally,
FOP
-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of
FOP
-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
...
PMID:8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. 1168 2
Constitutive activation of aberrant fibroblast growth factor receptor 1 (FGFR1) kinase as a consequence of gene fusion such as
FOP
-FGFR1 associated with t(6; 8)(q27;p11-12) translocation, is the hallmark of an atypical aggressive stem cell myeloproliferative disorder (MPD) in humans. In this study, we show that expression of
FOP
-FGFR1 in primary bone marrow cells induced by retroviral transduction generates a MPD in mice. Constitutive
FOP
-FGFR1 kinase activity was both essential and sufficient to cause a chronic myeloproliferative syndrome in the murine bone marrow transplantation model. In contrast to the human disorder, lymphoproliferation and progression to acute phase were not observed. Lymphoid symptoms, however, appeared when onset of the disease was delayed as the result of mutation of
FOP
-FGFR1 at tyrosine 511, the
phospholipase C
gamma (PLCgamma) binding site.
...
PMID:FOP-FGFR1 tyrosine kinase, the product of a t(6;8) translocation, induces a fatal myeloproliferative disease in mice. 1296 58
