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)

Interferon-stimulated gene factor 3 (ISGF3), the primary transcription factor induced by interferon alpha, is a complex of four (113, 91, 84, and 48 kd) proteins. This paper reports that the 113, 91, and 84 kd (ISGF3 alpha) proteins of ISGF3 contain conserved SH2 and SH3 domains. A specific interferon alpha-induced cytoplasmic protein tyrosine kinase(s) can form a transient complex with ISGF3 alpha proteins. These ISGF3 alpha proteins can be immunoprecipitated by anti-phosphotyrosine antibodies only after interferon alpha treatment. Phosphoamino acid analyses of 32P-labeled ISGF3 alpha proteins confirm that ISGF3 alpha proteins are directly tyrosine phosphorylated both in vitro and in vivo in response to interferon alpha, and this tyrosine phosphorylation can be inhibited by staurosporine and genistein. Phosphatase treatment of these ISGF3 alpha proteins results in inhibition of ISGF3 complex formation in vitro. These observations indicate that interferon alpha-induced direct tyrosine phosphorylation of ISGF3 alpha proteins is necessary for activation of the transcription factor ISGF3.
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PMID:A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). 163 33

Molluscum contagiosum is common in HIV disease and available therapies have a poor success rate and require frequent clinic visits. Interferon alpha has been used to treat recalcitrant condylomata acuminata and this study was undertaken to assess the use of this treatment in unresponsive molluscum contagiosum. A total of 30 molluscum contagiosum were injected with one megaunit of interferon alpha weekly for 4 weeks; 11 molluscum contagiosum completely cleared and 18 reduced in size by over 50%. Molluscum less than 0.5 cm in diameter, and those in patients without AIDS were more likely to respond. No surrounding lesions changed in size.
Int J STD AIDS
PMID:Intralesional interferon for the treatment of recalcitrant molluscum contagiosum in HIV antibody positive individuals--a preliminary report. 854 17

All-trans retinoic acid (ATRA) has recently been shown to synergize with the inhibitory effect of interferon alpha (IFN alpha) on the growth of malignant cells isolated from solid tumors. We investigated whether ATRA could potentiate the inhibitory effects of IFN alpha on the proliferation of leukemic progenitors in chronic myeloid leukemia (CML). CD34+ cells from chronic phase, newly diagnosed patients, were incubated in short-term liquid culture with ATRA, IFN alpha or a combination of both molecules and then plated on semi-solid cultures for colony-forming cell assay. IFN alpha was found to inhibit preferentially the generation of late progenitors. ATRA at a concentration of 10(-8) M was found strongly to inhibit CFU-M colonies. Addition of ATRA to IFN alpha dramatically potentiated the inhibitory effects of INF alpha on CFU-GM growth. In the presence of both molecules the inhibition of day 14 CFU-GM from CD34+ cells was lowered to 27 +/- 4% of control. CFU-M colonies were completely inhibited. RT-PCR analysis of the colonies resulting from the action of the combination IFN alpha plus ATRA showed the presence of an increased number of BCR-ABL-negative colonies relatively to what was observed with IFN alpha alone. FISH analysis showed a higher percentage of Ph-negative cells in the ATRA plus IFN alpha-treated samples, confirming PCR experiments. These results indicate that, in vitro, the combination of IFN alpha and ATRA effectively inhibits CFU-GM colony formation in CML and suggest that it has a potential interest for the treatment of CML.
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PMID:All-trans retinoic acid potentiates the inhibitory effects of interferon alpha on chronic myeloid leukemia progenitors in vitro. 918 Feb 90

This study was designed to determine whether the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway is activated in cardiac hypertrophy induced in vivo by pressure overload in rats and to demonstrate whether angiotensin II is involved in the activation of the JAK/STAT pathway. Acute pressure overload was produced by constricting the abdominal aorta of Wistar rats. Immunoprecipitation-Western blot analysis revealed that pressure overload activated JAK1, JAK2, and Tyk2 as early as 5 minutes and that STAT1, STAT2, and STAT3 were tyrosine-phosphorylated rapidly after exposure to the pressure overload. Phosphorylation of STAT1 and STAT2 peaked in the early stage at 5 to 15 minutes, whereas that of STAT3 peaked in the late stage at 60 minutes. Gel mobility shift of the interferon gamma activation site/interferon alpha-stimulating response element was observed immediately after the aortic banding, whereas the band of sis-inducing element was shifted in the late stage at 60 minutes. Both cilazapril (angiotensin II-converting enzyme inhibitor) and E4177 (angiotensin II type 1 [AT1] receptor antagonist) significantly suppressed the phosphorylation of Tyk2 and partially inhibited the phosphorylation of JAK2, but neither affected JAK1. Coimmunoprecipitation of the AT1 receptor with JAK2 or Tyk2 was clearly observed at 5 minutes and peaked at 15 minutes (20-fold the control value). These results indicate that the JAK/STAT pathway is activated by acute pressure overload in rats and that angiotensin II is involved in activating Tyk2, and partially activating JAK2, via the AT1 receptor. Both angiotensin II-dependent and -independent pathways take part in activating the JAK/STAT pathway in the pressure-overloaded rat heart.
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PMID:Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. 931 43

Donor leukocyte therapy has resulted in a remission rate in excess of 70% in patients with relapse of chronic myeloid leukaemia (CML) following allogeneic bone marrow transplantation (BMT). Induction of remission with donor leukocyte infusions has been primarily successful for CML patients who have cytogenetic relapse or those with chronic-phase haematological relapse. Response rates appear to be lower in patients who have advanced-phase CML. The majority of patients with CML who enter remission have no detectable minimal residual disease when analysed for BCR-ABL mRNA transcripts by reverse-transcription polymerase chain reaction. The efficacy of donor leukocyte infusions and the ease of therapy are balanced by the potential for significant toxicity. The reported treatment-related mortality rate is almost 20%. The major toxicities of this treatment are secondary to marrow aplasia and graft-versus-host disease (GVHD) which may occur in up to 50% and 90% of responders respectively. Donor leukocytes with a T-cell content of only 1 x 10(7)/kg, approximately a factor of 10 fewer T cells than used in most early studies, are capable of inducing remissions in some patients. The use of lower doses of T cells or CD8+ depleted T cells may be associated with less GVHD. The optimal treatment schedule using donor leukocytes has yet to be determined. Factors which might influence outcome include phase of disease, use of interferon alpha, use of unrelated donors and human leukocyte antigen disparity, T-cell dose, CD8+ depletion of leukocytes and time from BMT to leukocyte infusion.
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PMID:Donor leukocyte infusions. 937 69

In a retrospective single centre study we examined the outcome of five different therapy approaches in 48 patients in whom a relapse of CML (13 cytogenetic relapses, 35 hematological relapses: 10 chronic phase (CP), nine accelerated phase, 16 blast crisis) occurred after allogeneic BMT. Cyclosporin A (CsA) withdrawal, interferon alpha-2b (IFN-alpha) therapy, donor leukocyte transfusions (DLT), second transplantation (2nd BMT), and chemotherapy (CTX) alone were used and studied for their response rates. Patients who achieved a complete hematologic and cytogenetic remission (CR) were studied for BCR-ABL transcripts and for their chimerism status by PCR. A strong antileukemic effect was observed after abrupt CsA withdrawal, with 10 of 20 patients achieving a CR (50%). All 10 patients with early stage (nine cytogenetic and one CP), but none of the patients with advanced disease recurrence, responded to CsA withdrawal. IFN-alpha induced in five of 11 patients (45%) a stable cytogenetic remission, whereas treatment with DLT induced a CR in only two of 14 patients (14%). A second transplant was performed in six patients. Three of six patients (50%) survive disease-free at a median of 19 months after the 2nd BMT (range 10-25). The use of CTX alone did not induce a remission.
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PMID:A retrospective single centre study of the outcome of five different therapy approaches in 48 patients with relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation. 946 77

Cytogenetic, interphase fluorescent in situ hybridization (FISH) and RT-PCR methods were used to study minimal residual disease in peripheral blood stem cells collected for autografting in three chronic myeloid leukemia (CML) patients in sustained complete cytogenetic remission after treatment with interferon alpha (IFNalpha). Karyotypic analysis failed to reveal Ph-positive metaphases. FISH detected 9-16% nuclei with a BCR-ABL fusion gene, contrasting with RT-PCR, performed in two cases, which was negative in one case and weakly positive in the other. RT-PCR was also subsequently weakly positive in the third patient. This discrepancy suggests that the BCR-ABL genomic rearrangement persists unexpressed in quiescent cells. These preliminary results, which need to be confirmed in larger series, suggest that monitoring residual disease in CML should be performed both at DNA and RNA levels. Moreover, autografting following IFNalpha therapy should be considered with caution because of the persistence of the BCR-ABL genomic rearrangement in a sizeable proportion of the cells.
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PMID:Does BCR-ABL genomic rearrangement persist in CML patients in complete remission after interferon alpha therapy? 966 93

Cytokine signaling involves the activation of the Janus kinase (JAK) family of tyrosine kinases. These enzymes are physically associated with cytokine receptor components. Here, we sought to define the molecular basis of the interaction between Tyk2 and IFNAR1, a component of the interferon alpha/beta receptor, by delimiting a minimal IFNAR1 binding region in the Tyk2 protein. Using an in vitro assay system, we narrowed down the interaction domain to a region comprising the JH7 and part of the JH6 homology boxes (amino acids 22-221). When expressed in Tyk2-negative cells, the JH7-6 region was unable to stabilize IFNAR1 protein levels, a critical function that we previously attributed to the N region (amino acids 1-591) of Tyk2. Moreover, substitution of the JH7-JH6 domain in JAK1 with that of Tyk2 did not restore IFNAR1 level nor interferon alpha signaling in Tyk2-negative cells. Thus, the major interaction surface lies within JH7-6, but additional JH regions (JH5-4-3) contribute in a specific manner to the in vivo assembly of Tyk2 and IFNAR1. Evidence is also provided of the lack of specificity of the Tyk2 kinase-like and tyrosine kinase domains in interferon alpha/beta receptor signaling.
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PMID:Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1. 973 72

We report on a patient with Klinefelter's syndrome who underwent successful syngeneic peripheral blood stem cell transplantation (PBSCT) for chronic myelogenous leukemia (CML). A-46-year-old man was given a diagnosis of chronic phase CML in May 1994 on the basis of findings of leukocytosis (54,000/microliter) and bone marrow chromosomal abnormalities [47, XXY, t(9; 22; 14) (q34; q11; q24)]. Hydroxyurea and interferon alpha were administered. In August 1996, a syngeneic transplant was performed following myeloablative therapy, using peripheral blood stem cells collected from the patient's identical twin brother, who had been pretreated with rhG-CSF. Following transplantation (4.0 x 10(6) CD34+ cells/kg) and the subsequent administration of rhG-CSF, the patient rapidly achieved normal tri-lineage hematopoiesis. A post-transplant chromosomal analysis of the patient's bone marrow cells detected the 47, XXY karyotype. Although the major BCR-ABL gene had been detected in bone marrow by RT-PCR methods prior to the syngeneic PBSCT (August 1996), it was not detected after PBSCT (January 1997). In March 1998, interphase fluorescence in situ hibridization (FISH) procedures disclosed XXY signal patterns in peripheral blood lymphocyte samples from the patient and donor, at frequencies of 96% and 97%, respectively. Both the patient and donor had high levels of serum FSH and LH and low levels of serum testosterone.
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PMID:[Syngeneic peripheral blood stem cell transplantation for chronic myelogenous leukemia associated with Klinefelter's syndrome]. 1022 29

INTRODUCTION: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease due to a unique gene rearrangement event occurring within a pluripotent stem cell. The main characteristic of this mutation is the formation of a fusion gene (BCR-ABL) with increased tyrosine kinase activity from which a transforming activity for myelopoiesis derives. Clinically, CML is characterized by an initial chronic phase, followed by inevitable progression to an accelerated phase, and then to a terminal blastic phase. Allografting represents the only therapeutic procedure capable of curing the disease. Most centers currently use HLA-identical sibling transplants for patients less than 55 years of age. However, the majority of patients do not have an HLA-matched sibling donor. Matched or partially matched unrelated donor transplants are associated with a high transplant-related mortality within the first 100 days following the procedure. This approach should be offered to patients less than 50 years of age. Conventional therapy for CML includes hydroxyurea, busulfan and interferon alpha (IFN-&agr;). Conventional chemotherapy is unable to modify the natural history of the disease. On the contrary, recent randomized studies suggest that IFN-&agr; produces cytogenetic conversions to Philadelphia (Ph)-negative in some cases and may prolong overall survival [1-5]. Considering that the majority of Ph-negative patients maintain evidence of BCR/ABL positivity after IFN-&agr; therapy, it is unlikely that IFN-&agr; can cure the disease. In upcoming years, we must evaluate whether the high cost of IFN-&agr;, the poor tolerance of it in about one-fourth of treated patients, and the small chance of long-term benefit will be justified by a higher overall survival than with hydroxyurea. About 70% of CML patients do not have a matched family donor, and unrelated transplantation may produce high morbidity, particularly in older patients. For these patients and for those who do not achieve a cytogenetic remission after IFN-&agr; therapy, alternative treatment strategies are needed to increase disease-free survival. Autologous stem cell transplantation (ASCT) has been explored as an option for the treatment of these patients. In this review, we will focus on the recent update of this procedure, particularly on the in vivo manipulation technique.
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PMID:Autotransplants in Chronic Myeloid Leukemia. 1038 85


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