Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PEPSCAN analysis, performed using 536 overlapping nonapeptides derived from the HTLV-III B nucleotide sequence of the region encoding the external envelope protein of 120 kDa (gp120), identified in the V3 region of gp120 a major binding site for antibodies of HIV-1-infected humans. The minimal amino acid sequence of this antibody binding site was demonstrated by multiple length scanning to be five to eight amino acids in length: (G)PGRAF(VT), i.e. amino acids 312-319. A peptide (Neu 21) containing this binding site for human antibodies (KSIRIQRGPGRAFVTIG) was synthesized and shown to induce HTLV-III B cell fusion-inhibiting antibodies in rabbits and mice. Antibodies binding to this HTLV-III B/LAV-1-specific peptide were shown to be primarily of the IgG 1 subclass, appeared within 6 months after HIV-1 antibody seroconversion in six out of 14 men studied, and persisted throughout the follow-up period of 10-24 months. The other eight seroconverting men did not develop antibodies to Neu 21 during the observation period. The appearance of antibodies to Neu 21 paralleled the capacity of the serum to inhibit HTLV-III B in cell fusion. HIV-1-infected men with Kaposi's sarcoma exhibited a similar frequency of antibodies to the synthetic peptide Neu 21 (14 out of 39, 36%) as asymptomatic HIV-1-infected men (112 out of 319, 35%). Adults with Pneumocystis carinii pneumonia had a significantly lower frequency (11 out of 78, 14%) of antibodies to Neu 21. Similarly, a low prevalence of antibodies to Neu 21 (8 out of 43, 19%) was observed among symptomatic HIV-1-infected children.
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PMID:Human antibody response to a strain-specific HIV-1 gp120 epitope associated with cell fusion inhibition. 245 84

By transfecting high molecular weight DNA from a Kaposi sarcoma lesion into murine NIH 3T3 cells, we have identified and molecularly cloned a set of human DNA sequences capable of inducing focus formation, growth in agar, and tumorigenicity in these cells. The human DNA sequences present in primary, secondary, and tertiary NIH 3T3 transformants encompass about 32 kilobases (kb) and contain four rearrangements with respect to normal human DNA and a portion of the c-fms protooncogene (FMS in human gene nomenclature). However, the minimal transforming region (6.6 kb) identified in our cloned DNA borders on the c-fms DNA region but does not contain c-fms coding sequences. The fms sequences are also not represented in the two transcripts (approximately equal to 1.2 and 3.5 kb) detected in NIH 3T3 transformants; however, they might provide elements regulating expression. Hybridization to several known oncogene probes and preliminary sequencing data indicate that we have identified a previously unrecognized "activated" oncogene. Since the rearrangements present in our cloned DNA sequences are not detectable in the original Kaposi tumor DNA used for transfection, it is possible that this oncogene was generated during gene transfer.
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PMID:Isolation of a rearranged human transforming gene following transfection of Kaposi sarcoma DNA. 347 97

To define the histogenesis and cell origin of Kaposi sarcoma (KS), we cultured KS cells without retrovirally conditioned media from three HIV seropositive AIDS patients and then attempted to raise mouse hybrid monoclonal antibodies (Mabs) specific to these AIDS-KS cells. After both in vivo and in vitro immunization trials, all putative Mabs reacted positively to KS cells but also non-specifically with other human (CH5 and OM) and non-human (RSE-1) control endothelial cell lines. To overcome this crossreactivity, we further "absorbed" previously cloned hybrids and pre-hybrid splenocytes by incubating them with the control endothelial cell lines to eliminate splenocytes and/or hybridomas reactive to normal endothelium. Whereas absorption successfully eliminated immunoreactivity to control endothelium, it also excluded reactivity to KS cells. These findings (lack of specific antigenicity and immunoresponsiveness of KS similar to non-KS control endothelium) suggest that AIDS-KS cells are neither antigenically transformed nor neoplastic, but instead represent dedifferentiated or transdifferentiated endothelium which retains immunogenicity of its original endothelial cell prototype.
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PMID:Absence of monoclonal antibody detectable Kaposi sarcoma-specific antigens on lesion-derived cultured cells. 842 58

Kaposi's sarcoma is a highly vascularized multifocal tumor which frequently appears as a complication of HIV infection. It has been suggested that a disorder in the cytokine network may contribute to the development of the disease. We examined the expression of several cytokines in human sporadic Kaposi's-sarcoma specimens, as well as in spindle cells cultured from human lesions, and consistently found high levels of expression of hepatocyte growth factor (HGF). In addition, human lesion-derived spindle cells synthesize and secrete biologically active hepatocyte growth factor and express the hepatocyte-growth-factor receptor (c-MET). Moreover, elevated levels of transforming growth factor beta 1 (TGF beta 1) mRNA were found in lesions of human sporadic Kaposi's sarcoma and in lesion-derived spindle cells which also over-express urokinase. Since HGF, TGF beta 1 and urokinase are all involved in capillary-vessel organization, dysregulation of these interacting agents may play a role in the initiation and/or progression of Kaposi's sarcoma, stimulating the growth of spindle cells and recruiting endothelial cells into the lesion.
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PMID:Over-expression of hepatocyte growth factor in human Kaposi's sarcoma. 856 12

The HIV-1 Tat protein transactivates HIV, viral and some host cell genes. Tat can be released by infected cells and acts extracellularly in the microenvironment, regulating functions of immunocompetent and mesenchymal cells. One of the most striking effects of Tat is the induction of a functional program in vascular cells related to angiogenesis and inflammation (migration, proliferation and expression of plasminogen activator inhibitor-1 and E selectin). Tat induces growth of Kaposi's sarcoma (KS) spindle cells and is angiogenic in vivo and in transgenic mice10-12. We previously reported that Tat is a direct angiogenic factor and noted the Tat arginine- and lysine-rich sequence is similar to that of other potent angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). It is possible that Tat mimics one of these factors by interacting with its growth factor tyrosine kinase receptor. Here we demonstrate that Tat specifically binds and activates the Flk-1/kinase insert domain receptor (Flk-1/KDR), a VEGF-A tyrosine kinase receptor (for review see ref. 13), and that Tat-induced angiogenesis is blocked by agents blocking the Flk-1/KDR receptor. Endothelial cell stimulation by Tat occurs in the absence of activation of FLT-1, another VEGF-A tyrosine kinase receptor.
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PMID:The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. 894 38

Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection and develops in nearly 30% of cases. The principal features of this tumor are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. KS-derived spindle cells induce vascular lesions and display enhanced vascular permeability when inoculated subcutaneously in the nude mouse. This finding suggests that angiogenesis and capillary permeability play a central role in the development and progression of KS. In this study, we show that AIDS-KS cell lines express higher levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VGF) than either human umbilical vein endothelial cells or human aortic smooth muscle cells. AIDS-KS cells and primary tumor tissues also expressed high levels of Flt-1 and KDR, the receptors for VEGF, while the normal skin of the same patients did not show any expression. We further demonstrate that VEGF antisense oligonucleotides AS-1 and AS-3 specifically block VEGF mRNA and protein production and inhibit KS cell growth in a dose-dependent manner. Furthermore, growth of KS cells in nude mice was specifically inhibited by VEGF antisense oligonucleotides. These results show that VEGF is an autocrine growth factor for AIDS-KS cells. To our knowledge, this is the first report that shows that VEGF acts as a growth stimulator in a human tumor. Inhibitors of VEGF or its cognate receptors may thus be candidates for therapeutic intervention.
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PMID:Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. 902 68

Kaposi's sarcoma (KS) spindle cell growth and spread have been reported to be modulated by various cytokines as well as the human immunodeficiency virus (HIV) gene product Tat. Recently, HIV-1 Tat has been shown to act like a cytokine and bind to the Flk-1/KDR receptor for the vascular endothelial growth factor A (VEGF-A), which is expressed by KS cells. We have characterized signal transduction pathways stimulated by HIV-1 Tat upon its binding to surface receptors on KS cells. We observed that stimulation in KS 38 spindle cells resulted in tyrosine phosphorylation and activation of the Flk-1/KDR receptor. We also report that HIV-1 Tat treatment enhanced the phosphorylation and association of proteins found in focal adhesions, such as the related adhesion focal tyrosine kinase RAFTK, paxillin, and p130(cas). Further characterization revealed the activation of mitogen-activated protein kinase, c-Jun amino-terminal kinase (JNK), and Src kinase. HIV-1 Tat contains a basic domain which can interact with growth factor tyrosine kinase receptors and a classical RGD sequence which may bind to and activate the surface integrin receptors for fibronectin and vitronectin. We observed that stimulation of KS cells with basic as well as RGD sequence-containing Tat peptides resulted in enhanced phosphorylation of RAFTK and activation of MAP kinase. These studies reveal that Tat stimulation activates a number of signal transduction pathways that are associated with cell growth and migration.
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PMID:Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. 962 Oct 77

Recently, the expression of fibroblast growth factor 3 (FGF3) was found in 55% of human Kaposi's sarcoma (KS) tumor tissues examined, while almost no expression of FGF3 was found in normal skin. To further these studies, human FGF3 cDNA were constructed by the overlap-extension method. The proteins translated from two FGF3 cDNA, which differ only in the sequences preceding the AUG presumed to be the initiation codon, were shown to have the same molecular mass. This result suggests that translation of human FGF3, which is different from mouse FGF3, begins only at the AUG site. The human FGF cDNA was transfected into NIH3T3 cells. The NIH 3T3 cells transformed by FGF3 were then injected subcutaneously into athymic nude mice. Nodular lesions developed at the injection sites in all seven mice injected with the F3-1 cell clone, which showed high expression of FGF3, and in two out of six mice injected with the F3-2 cell clone, which expressed a low level of FGF3. Histopathological features of these tumors contained fascicles of spindle-shaped cells surrounding irregular endothelial lined vascular clefts, similar to those observed in human KS lesions. Immunohistochemical staining for factor V111 antigen revealed reactivity in multiple areas, especially in abundant vascular structures of the tumor sections examined. The expression of FGF3 together with the FGF receptors FGFR1, FGFR2, and FGFR3, was detected in the mouse tumors by Northern blot analysis. Our results indicate that tumors induced by FGF3-transformed NIH3T3 cells show some similarities to human KS tumors. In conclusion, our results demonstrate the potential tumorigenic and angiogenic role of human FGF3.
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PMID:Evaluation of the tumorigenic and angiogenic potential of human fibroblast growth factor FGF3 in nude mice. 964 56

Angiogenesis is a critical step in a benign tumor's evolution toward malignancy and metastasis. Tumor cells acquire such a phenotype by their ability to secrete angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF receptors (VEGFRs) flt-1/VEGFR-1 and Flk-1/ KDR/VEGFR-2 are restricted to activated endothelial cells, with the highest expression being in the tumor vasculature. The present study was undertaken to target the VEGFRs. Targeted toxins were developed by recombinant methods by fusing VEGF165 or VEGF121 to the diphtheria toxin (DT) translocation and enzymatic domain (DT390-VEGF165 or DT390-VEGF121). Both fusion proteins were found to be highly toxic to proliferating endothelial cells but not to vascular smooth muscle cells. The fusion protein is also active in Kaposi's sarcoma, a tumor type that expresses high levels of VEGFRs. These fusion proteins completely inhibit the basic fibroblast growth factor-induced growth of new blood vessels in the chick chorioallantoic membrane assay. Furthermore, the fusion toxin substantially retards the growth of Kaposi's sarcoma tumors in mice. Because nearly all tumors induce local angiogenesis with high VEGFR expression, VEGF-derived toxins may have wide application in cancer therapy.
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PMID:Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells. 989 5

A recently identified herpesvirus, human herpesvirus-8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, has been found in nonmalignant bone marrow dendritic cells of patients with multiple myeloma. The virus is also detectable in the peripheral blood of most patients; its absence suggests earlier-stage disease. HHV-8 is not detected in the blood of family members and sexual partners of myeloma patients. Sequencing of HHV-8 open-reading frames (ORFs) shows differences between individual myeloma patients, as well as between myeloma patients and those with other HHV-8-related malignancies. Consistent expression of the viral homolog of both interferon regulatory factor (IRF) and interleukin-8 receptor (IL-8R) suggests a possible role for these transforming viral genes in the pathogenesis of myeloma. Detailed analysis of myeloma cell lines has shown that myeloma is characterized by frequent chromosome translocations involving the switch regions of the immunoglobulin heavy-chain (IgH) locus on 14q32. The three partner chromosomes most commonly involved are 11q13 (cyclin D1), 4p16 (FGFR3), and 16q23 (c-maf). Mutations have also been identified in N- and K-ras and, less frequently, involving p53. Monosomy 13q is common. These findings have implications for immunotherapy. Angiogenesis increases with progressive disease and appears to be a prognostic factor. In at least one patient, this process appears to have been reversed with thalidomide therapy. The underlying mechanisms for the increased vascularization in myeloma have not been identified, and several possibilities have been proposed.
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PMID:Initiation and maintenance of multiple myeloma. 998 83


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