Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors. The CIS family of proteins (also referred as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Among them, we have shown that JAB/SOCS-1 is strongly induced by interferon-gamma and forced expression of JAB/SOCS-1I conferred cells interferon resistance. This resistance was caused by inhibition of JAK1 and JAK2 activation in response to IFNgamma. Moreover, recent detailed analysis of JAB/SOCS-1 knockout mice revealed that JAB/SOCS-1 is indeed a "negative feedback regulator" that determine the sensitivity of cells to IFNgamma. Using in vitro mutagensis, we defined a functional structure of JAB/SOCS-1 and proposed a mechanism for how JAB inhibits JAK kinase activity.
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PMID:The janus kinase inhibitor, Jab/SOCS-1, is an interferon-gamma inducible gene and determines the sensitivity to interferons. 1081 47

Reverse transcription polymerase chain reaction (RT-PCR) analysis is increasingly becoming part of the diagnostic and prognostic evaluation for hematologic and oncologic disorders. Currently, different RNA isolation methods are used in the diagnostic laboratories. No data are available on their suitability for sensitive detection of breakpoint cluster region-abelson (BCR-ABL) gene transcripts. We have extracted RNA from mononuclear cell (MNC) fractions and from lysed blood samples of 4 patients (1 with leukocytosis, 1 with chronic myelogeneous leukemia (CML) under interferon treatment, and 2 CML patients after bone marrow transplantation) with 3 RNA isolation reagents (TRIzol, RNAzol, FastTube reagent). RNA yield was slightly higher with RNAzol than with TRIzol as indicated by agarose gel electrophoresis and spectrophotometric measurement at 260 nm. The FastTube reagent was unsuitable for RNA isolation from MNC, and was not evaluated for lysed blood. Quantitative competitive RT-PCR amplification of the ABL gene showed comparable results for RNA isolated with RNAzol and TRIzol. In RNA samples extracted from lysed whole blood, the presence of amplifiable RNA/cDNA was confirmed by amplification of 4 selected reference genes (porphobilinogen deaminase (PBGD), ABL, the gene spanning the BCR on chromosome 22 and retinoic acid receptor alpha (RARA)) in a multiplex PCR. High quality, DNA-free RNA was obtained with RNAzol, and 1 BCR-ABL-positive (specific for translocation t [9; 221) cell among 2x10(4) normal cells was successfully detectable by single step RT-PCR. In RNA isolated with TRIzol, major contaminations with genomic DNA were observed which significantly impaired the interpretation of the results of RT-PCR analysis.
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PMID:Evaluation of RNA isolation methods and reference genes for RT-PCR analyses of rare target RNA. 1083 6

We have identified an interferon-like cytokine, limitin, on the basis of its ability to arrest the growth of or kill lympho-hematopoietic cells. Limitin strongly inhibited B lymphopoiesis in vitro and in vivo but had little influence on either myelopoiesis or erythropoiesis. Because limitin uses the interferon alpha/beta receptors and induces interferon regulatory factor-1, it may represent a previously unknown type I interferon prototype. However, preferential B-lineage growth inhibition and activation of Janus kinase 2 in a myelomonocytic leukemia line have not been described for previously known interferons.
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PMID:Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors. 1083 82

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

Chronic hypoxia up-regulated the mRNA and protein expression of inducible nitric oxide synthase (iNOS) in EMT-6 tumour cells exposed to interferon (IFN)-gamma and interleukin (IL)-I beta. Low concentrations of cytokines (1 unit ml(-1)) in 1% but not in 21% oxygen induced a remarkable increase in NO production and a 1.8-fold hypoxic cell radiosensitization. Therefore, chronic hypoxia may potentially be exploited to increase tumour cell radioresponse through the cytokine-inducible iNOS pathway.
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PMID:Chronic hypoxia modulates tumour cell radioresponse through cytokine-inducible nitric oxide synthase. 1130 64

Anal intraepithelial lesions (ASILs) are considered as precursors of anal cancer. The incidence of high-grade ASIL (HSIL) and progression of low-grade ASIL (LSIL) to HSIL are high in HIV-positive men. Endogenous cytokines, such as interferons (IFNs) play an important role in the regulation of proliferation and immune responses in epithelial cells, and thus, they might control the above-mentioned progression events. Accordingly, we determined mRNA levels of IFN-gamma and IFN-gamma receptors, levels of IFN-gamma receptor-associated kinases (JAK1 and TYK2) and signalling molecules (signal transducer and activator of transcription-1 [STAT1], STAT3, interferon-responsive-factor-1 [IRF-1] and IRF-2) as well as inhibitors of cytokine signalling (protein inhibitor of activated STAT1 [PIAS1] and suppressor of cytokine signalling 2 [SOCS2]) in biopsies of anal condylomas, LSILs as well as HSILs from HIV-positive individuals by a semi-quantitative reverse transcribed polymerase chain reaction (RT-PCR) method. We found that HSIL significantly differs in expression of these genes from LSIL and condylomas. Expression profile of HSIL samples showed activation of STAT3 signalling, probably accounting for the observed high levels of genes that support cellular proliferation (IRF-2, c-fos and c-myc). Decreases in levels of suppressors (IFN-gamma and IRF-1) and JAK1 kinase, but increases in levels of inhibitors of cytokine signalling (PIAS1 and SOCS2) might also contribute to the altered cytokine signalling in HSIL biopsies. These findings might reveal important molecular events associated with progression of LSIL to HSIL in HIV-infected men.
Int J STD AIDS 2001 Apr
PMID:The endogenous interferon system in anal squamous epithelial lesions with different grades from HIV-positive individuals. 1131 73

Chronic hepatitis B infection is frequently diagnosed within the genitourinary clinic setting with sexual transmission the commonest route of acquisition in the United Kingdom. Only 3--5% of adults who contract acute hepatitis B will progress to chronic infection, and these individuals can be identified by the presence of hepatitis B surface antigen (HBsAg) in the bloodstream 6 months after infection. Individuals at highest risk of long-term complications such as cirrhosis and hepatocellular carcinoma, carry HBeAg and have high levels of circulating hepatitis B virus (HBV) deoxyribonucleic acid (DNA). Therapy should be targeted towards this group of patients. Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine. Seroconversion occurs in 30--40% of patients treated with interferon and treatment is often limited by toxicity. Lamivudine is well tolerated with seroconversion rates of 15--20% at one year, rising with increasing duration of therapy. Long-term monotherapy is limited however by the development of resistance mutations and combination nucleoside therapy is likely to become the treatment of choice in the future. Patients with chronic hepatitis B should be counselled regarding transmission, partner vaccination and alcohol intake and co-infection with other hepatitis viruses should be excluded.
Int J STD AIDS 2001 Jun
PMID:The management of chronic hepatitis B infection. 1180 40

STI571 selectively inhibits the ABL-tyrosine kinase, the activity of which is activated by the formation of chimeric BCR/ABL. A phase I study in the USA showed STI571 to be remarkably effective in cases of interferon-refractory chronic myeloid leukemia, with almost no adverse effects. STI571 may become the first choice drug prior to stem cell transplantation and interferon treatment.
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PMID:[Tyrosine kinase inhibitor--hematological malignancies]. 1138 7

A major deletion of the region proximal to the rearranged ABL gene on 9q was found in 14/94 (15%) of chronic myelogenous leukemia Philadelphia-positive patients by interphase fluorescent in situ hybridization with the BCR/ABL extra signal dual-color probe. Preliminary results indicated that the prognosis of the deletion 9q patients is probably worse than that of the non-deletion 9q patients. Twelve of the 14 deletion 9q patients were treated with alpha-interferon and none had a major cytogenetic response. The median duration of the chronic phase in patients not undergoing BMT was significantly shorter for the deletion 9q patients as compared to the non-deletion 9q patients (p =.0144). DNA microarray technology was performed in order to compare the gene expression patterns between the two groups of patients. A number of genes exhibiting differential expression, especially involving cell adhesion and migration, were identified. This finding may identify a sub-group of CML patients with different cell properties and a relatively poor prognosis.
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PMID:Subgroup of patients with Philadelphia-positive chronic myelogenous leukemia characterized by a deletion of 9q proximal to ABL gene: expression profiling, resistance to interferon therapy, and poor prognosis. 1146 49

The avian homologue of the interferon regulatory factor 4 (IRF-4) and a novel splice variant lacking exon 6, IRF-4DeltaE6, were isolated and characterized. Chicken IRF-4 is expressed in lymphoid organs, less in small intestine, and lungs. IRF-4DeltaE6 mRNA, though less abundant than full-length IRF-4, was detected in lymphoid tissues, with the highest levels observed in thymic cells. IRF-4 is highly expressed in v-Rel-transformed lymphocytes, and the expression of IRF-4 is increased in v-Rel- and c-Rel-transformed fibroblasts relative to control cells. The expression of IRF-4 from retrovirus vectors morphologically transformed primary fibroblasts, increased their saturation density, proliferation, and life span, and promoted their growth in soft agar. IRF-4 and v-Rel cooperated synergistically to transform fibroblasts. The expression of IRF-4 antisense RNA eliminated formation of soft agar colonies by v-Rel and reduced the proliferation of v-Rel-transformed cells. v-Rel-transformed fibroblasts produced interferon 1 (IFN1), which inhibits fibroblast proliferation. Infection of fibroblasts with retroviruses expressing v-Rel resulted in an increase in the mRNA levels of IFN1, the IFN receptor, STAT1, JAK1, and 2',5'-oligo(A) synthetase. The exogenous expression of IRF-4 in v-Rel-transformed fibroblasts decreased the production of IFN1 and suppressed the expression of several genes in the IFN transduction pathway. These results suggest that induction of IRF-4 expression by v-Rel likely facilitates transformation of fibroblasts by decreasing the induction of this antiproliferative pathway.
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PMID:Interferon regulatory factor 4 contributes to transformation of v-Rel-expressing fibroblasts. 1153 27


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