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

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We had previously observed that HPV-16 E7 disturbs the Guanylate Binding Protein (GBP)-ISRE reporter activation by IFN-gamma thus suggesting an alteration of the IRF-1 function. In this study we examined the mechanism by which E7 affects the IFN-gamma signals driving the activation of gene transcription. Using 14/2 BRK cells containing dexamethasone-inducible HPV-16 E7 gene, we observed a large inhibition of the IRF-1 DNA binding activity upon E7 induction. Concomitantly, there was no significant change in the levels of IRF-1, indicating that this was not due to reduced levels of IRF-1 expression. Likewise, in vitro translated E7 did not affect the IRF-1 DNA binding activity in nuclear extracts derived from IFN-induced cells, thus indicating that the effects of E7 are upstream of IRF-1's binding to its DNA recognition site. Finally, NFkappaB DNA binding activity was also inhibited under conditional expression of E7. These data indicate that HPV-16 E7 inhibits the IRF-1 and NFkappaB function and this could lead to the impairment of the IFN response in HPV-infected cells. Furthermore, the findings suggest that different events of the IFN inducible signal cascade seem to be target for HPV-16 E7.
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PMID:Human papillomavirus type 16 E7 impairs the activation of the interferon regulatory factor-1. 1081 19

Hematopoietic progenitor cells from Fanconi anemia (FA) group C (FA-C) patients display hypersensitivity to the apoptotic effects of gamma interferon (IFN-gamma) and constitutively express a variety of IFN-dependent genes. Paradoxically, however, STAT1 activation is suppressed in IFN-stimulated FA cells, an abnormality corrected by transduction of normal FANCC cDNA. We therefore sought to define the specific role of FANCC protein in signal transduction through receptors that activate STAT1. Expression and phosphorylation of IFN-gamma receptor alpha chain (IFN-gammaRalpha) and JAK1 and JAK2 tyrosine kinases were equivalent in both normal and FA-C cells. However, in coimmunoprecipitation experiments STAT1 did not dock at the IFN-gammaR of FA-C cells, an abnormality corrected by transduction of the FANCC gene. In addition, glutathione S-transferase fusion genes encoding normal FANCC but not a mutant FANCC bearing an inactivating point mutation (L554P) bound to STAT1 in lysates of IFN-gamma-stimulated B cells and IFN-, granulocyte-macrophage colony-stimulating factor- and stem cell factor-stimulated MO7e cells. Kinetic studies revealed that the initial binding of FANCC was to nonphosphorylated STAT1 but that subsequently the complex moved to the receptor docking site, at which point STAT1 became phosphorylated. The STAT1 phosphorylation defect in FA-C cells was functionally significant in that IFN induction of IFN response factor 1 was suppressed and STAT1-DNA complexes were not detected in nuclear extracts of FA-C cells. We also determined that the IFN-gamma hypersensitivity of FA-C hematopoietic progenitor cells does not derive from STAT1 activation defects because granulocyte-macrophage CFU and erythroid burst-forming units from STAT1(-/-) mice were resistant to IFN-gamma. However, BFU-E responses to SCF and erythropoietin were suppressed in STAT(-/-) mice. Consequently, because the FANCC protein is involved in the activation of STAT1 through receptors for at least three hematopoietic growth and survival factor molecules, we reason that FA-C hematopoietic cells are excessively apoptotic because of an imbalance between survival cues (owing to a failure of STAT1 activation in FA-C cells) and apoptotic and mitogenic inhibitory cues (constitutively activated in FA-C cells in a STAT1-independent fashion).
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PMID:The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. 1084 98

The purpose of this study was to determine whether interferon-gamma (IFN-gamma) induced CD69 expression by eosinophil precursors. Eosinophil precursors were induced from CD34+ cord blood cells using recombinant human interleukin-3 (IL-3) and interleukin-5 (IL-5). On day 14 of culture, cells constitutively expressed CD69 and the IFN-gamma receptor (IFN-gammaR). Stimulation with IFN-gamma for 24 h did not affect IFN-gammaR expression by the cells. On the other hand, IFN-gamma significantly upregulated CD69 expression by the precursors after 24 h of incubation. A specific JAK2 inhibitor (AG-490) caused a concentration-dependent suppression of IFN-gamma-induced CD69 expression by the precursors. In conclusion, these results indicate that IFN-gamma induces CD69 expression by eosinophil precursors via the activation of JAK2.
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PMID:Regulation of CD69 expression on eosinophil precursors by interferon-gamma. 1086 4

We have previously shown that interferon-alpha (IFN alpha)-dependent tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired by serine phosphorylation of IRS-1 due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for Janus kinase 1 (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70(s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1(511-772)). Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFN alpha-dependent tyrosine phosphorylation by twofold while reducing constitutive IRS-1 serine phosphorylation within S/T-P motifs by 80%. Taken together, these data indicate that FRAP, but not p70(s6k), is a likely physiologic IRS-1 serine kinase that negatively regulates JAK1-dependent IRS-1 tyrosine phosphorylation and suggests that FRAP may modulate IRS-dependent cytokine signaling.
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PMID:Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. 1116 88

Polyomavirus (PyV) infection induces protective T-cell-independent (TI) IgM and IgG responses in T-cell-deficient (TCR beta x delta-/-) mice. In this study, we show that PyV is a TI -2 antigen: B cells with a mutated Bruton's tyrosine kinase (Xid mutants) do not respond to PyV with antibody secretion in the absence of T cells. We also demonstrate that NK-cell-mediated "help" is not absolutely required for the induction of the TI-2 antibodies to PyV; thus for the first time, we provide evidence for protective IgM and IgG responses against a viral infection induced in mice lacking T and NK cells (CD3Etg). Comparison of the antibody responses observed in T- and NK-cell-deficient mice with those of mice lacking only T cells, however, suggests that NK cells may promote isotype switching to IgG2a. This effect is probably mediated by IFN gamma secretion. In support of this idea, studies on the antibody responses of PyV-infected SCID mice that had been reconstituted with IFN gamma R-/- B cells or wild-type B cells demonstrated the IFN gamma dependence of PyV-specific TI IgG2a secretion and provided evidence that IFN gamma acting directly on B cells plays an important role in TI pathways of isotype switching to IgG2a in vivo.
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PMID:Antiviral T-cell-independent type 2 antibody responses induced in vivo in the absence of T and NK cells. 1116 30

Interferon alpha (IFNalpha) has significant clinical activity in the treatment of patients with chronic myelogenous leukaemia (CML), but the mechanisms of its selective efficacy in the treatment of the disease are unknown. The CrkL adaptor protein interacts directly with the BCR-ABL fusion protein that causes the malignant transformation and is constitutively phosphorylated in BCR-ABL-expressing cells. In the present study, we provide evidence that CrkL was engaged in IFNalpha-signalling in the CML-derived KT-1 cell line, which expresses BCR-ABL and is sensitive to the growth inhibitory effects of IFNalpha. CrkL is constitutively associated with BCR-ABL in these cells and treatment with IFNalpha had no effect on the BCR-ABL/CrkL interaction. After IFNalpha stimulation, CrkL associated with Stat5, which also underwent phosphorylation in an IFNalpha-dependent manner. The interaction of CrkL with Stat5 was facilitated by the function of both the SH2 and the N-terminus SH3 domains of CrkL. The resulting CrkL-Stat5 complex translocated to the nucleus and could be detected in gel shift assays using elements derived from either the beta-casein promoter or the promoter of the PML gene, an IFNalpha-inducible gene that mediates growth inhibitory responses. In addition to its interaction with Stat5, CrkL interacts with C3G in KT-1 cells and such an interaction regulates the downstream activation of the small GTPase Rap1, which also mediates inhibition of cell proliferation. Thus, despite its engagement by BCR-ABL in CML-derived cells, CrkL mediates activation of downstream signalling pathways in response to the activated type I IFN receptor and such signals may contribute to the generation of the anti-proliferative effects of IFNalpha in CML.
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PMID:Engagement of the CrkL adaptor in interferon alpha signalling in BCR-ABL-expressing cells. 1116 25

The mechanism and target cell of the life-prolonging effect of interferon-alpha (IFN-alpha) in chronic myelogenous leukemia (CML) are controversial. We studied the influence of IFN-alpha treatment on the frequency of malignant hematopoietic precursor cells in the peripheral blood (PB) of CML patients during the course of the disease. PB 10-day colony-forming cells (PB-CFCs) were assessed with regard to their quantity, lineage distribution, and BCR-ABL status, as determined by fluorescence in situ hybridization (FISH). PB-CFC numbers were determined in 39 patients (29 in the chronic phase, 6 in an advanced stage, and 4 with progression to an advanced stage during follow-up). Thirty-one patients were evaluated either once or several times to determine the BCR-ABL status of the colonies. BCR-ABL negative PB-CFCs were detectable at diagnosis in 5 of 11 patients. A major reduction of BCR-ABL positive colonies to <25% of PB-CFCs was observed in 10/13 determinable IFN-alpha treated patients in early and late chronic phases, indicating a high proportion of BCR-ABL negativity at the clonogenic cell level. In contrast, only 3 of these patients had a cytogenetic response of <25% Philadelphia chromosome (Ph1)-positive metaphases in bone marrow cytogenetics. Treatment with IFN-alpha and/or hydroxyurea (HU) during chronic phase was accompanied by a reduction of PB-CFCs to subnormal levels (median 24 CFCs/ml) compared to controls (median 207 CFCs/ml), untreated patients in chronic phase (median 25,979 CFCs/ml), and patients with advanced disease (median 6,047 CFCs/ml). In blast crisis (6 patients), all colonies tested were BCR-ABL positive. Our results show that IFN-alpha treatment leads to a marked reduction of malignant myeloid precursor cells in the PB of CML patients, which exceeds the degree of cytogenetic remission. This offers an explanation for the good therapeutic efficacy and even life-prolonging effect of IFN-alpha, which is also observed in cytogenetic non-responders.
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PMID:Predominantly BCR-ABL negative myeloid precursors in interferon-alpha treated chronic myelogenous leukemia: a follow-up study of peripheral blood colony-forming cells with fluorescence in situ hybridization. 1123 81

The mechanisms by which interferon-alpha (IFN-alpha) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-alpha in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-alpha treatment induced phosphorylation/activation of p38 in the IFN-alpha-sensitive KT-1 cell line, but not in IFN-alpha-resistant K562 cells. Consistent with this, IFN-alpha treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-alpha-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-alpha signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-alpha responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-alpha. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-alpha-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-alpha, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-alpha inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-alpha in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-alpha in CML cells.
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PMID:The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells. 1135 67

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-alpha) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-alpha receptor (IFN-alphaR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-alpha monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-alphaR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-alpha. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-alpha was observed. In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases). Median values of IFN-alphaR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P =.037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% +/- 17% at 24 months; P =.0001). (Blood. 2001;97:3568-3573)
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PMID:Expression of interferon-alpha (IFN-alpha) receptor 2c at diagnosis is associated with cytogenetic response in IFN-alpha-treated chronic myeloid leukemia. 1136 52

STAT1 must be phosphorylated on serine 727 to be fully active in transcription. We show that phosphatidylinositol 3-kinase (PI3K) and its effector kinase Akt play an important role in the serine phosphorylation of STAT1 and in the activation of gene expression in response to interferon-gamma (IFN gamma). IFN gamma activates PI3K as well as Akt in a variety of cell lines. Specific inhibition of PI3K abrogates IFN gamma-induced, but not interleukin-1- or tumor necrosis factor-alpha-induced, phosphorylation of STAT1 on serine and reduces STAT1-dependent transcription and gene expression by approximately 7-fold. Constitutively active forms of PI3K or Akt activate and their dominant-negative derivatives inhibit STAT1-driven transactivation in response to IFN gamma. In addition to PI3K and Akt, JAK1, JAK2, and the tyrosine 440 STAT1 docking residue of IFNGR1 are required for STAT1 to be phosphorylated on serine. Taken together, these results suggest that the following events lead to the activation of STAT1 upon IFN gamma stimulation: 1) PI3K and Akt are activated by the occupied receptor and Tyr-440 is phosphorylated by the activated JAKs; 2) STAT1 docks to Tyr-440; and 3) Tyr-701 is phosphorylated by the JAKs and Ser-727 is phosphorylated by a kinase downstream of Akt.
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PMID:Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. 1143 44


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