Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus-1 (HIV-1)-Tat, the transactivating gene product of HIV-1, has been shown to interact with different cell types, inducing gene expression, altering their growth and migratory behavior. In this study we examined whether Tat might affect functions of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL), relevant to the in vivo dissemination. Our results show that Tat significantly augmented the motility of the two AIDS-related Burkitt's lymphoma cell lines (AS283 and PA682PB) and AIDS-primary effusion lymphoma cell line (HBL-6-AIDS-PEL). Mutations in RGD or basic domain of Tat (KGE-MBP and LxI-MBP, respectively) sharply reduced migration compared with wild type, suggesting that both domains are required for migration. In contrast, a Tat protein mutation outside the active domains (NH(2)-TAT-GST) did not reduce lymphoma cell migration. The treatment of lymphoma cells with Tat did not influence their adhesion to matrix proteins or to human vascular endothelial cells, but endothelial cells treated with Tat became more adhesive to lymphoma cells. Flow cytometric analysis showed that treatment of endothelial cells with Tat induced the cell surface expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and E-selectin and increased the expression of intercellular adhesion molecule-1 (ICAM-1). Only antibodies against VCAM-1 on endothelial cells or against the VLA-4 integrin expressed on AS283 cells inhibited the increment of adhesion, indicating the relevance of this pathway in the adhesion of lymphoma cells to vascular endothelium. In our work, we show for the first time that Tat can enhance the migration of lymphoma cells and their adhesion to endothelial cells, two processes that may contribute to the malignant behavior of NHL in patients with AIDS.
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PMID:Human immunodeficiency virus-1 (HIV-1)-Tat protein promotes migration of acquired immunodeficiency syndrome-related lymphoma cells and enhances their adhesion to endothelial cells. 1047

Advanced-stage peritoneal carcinomatosis is resistant to current chemotherapy treatment and, in the case of metastatic ovarian cancer, results in a devastating 15%-20% survival rate. Therapeutics that restore genes inactivated during oncogenesis are predicted to be more potent and specific than current therapies. Experiments with viral vectors have demonstrated the theoretical utility of expressing the p53 tumor suppressor gene in cancer cells. However, clinically useful alternative approaches for introducing p53 activity into cancer cells are clearly needed. It has been hypothesized that direct reactivation of endogenous p53 protein in cancer cells will be therapeutically beneficial, but few tests of this hypothesis have been carried out in vivo. We report that a transducible D-isomer RI-TATp53C' peptide activates the p53 protein in cancer cells, but not normal cells. RI-TATp53C' peptide treatment of preclinical terminal peritoneal carcinomatosis and peritoneal lymphoma models results in significant increases in lifespan (greater than 6-fold) and the generation of disease-free animals. These proof-of-concept observations show that specific activation of endogenous p53 activity by a macromolecular agent is therapeutically effective in preclinical models of terminal human malignancy. Our results suggest that TAT-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to malignant cells in vivo.
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PMID:Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. 1496 35

Asparaginase (ASNase) is an enzyme drug presently approved for the induction of remission in the treatment of patients with acute lymphoblastic leukemia (ALL). The cytotoxic effect of ASNase is derived from its ability to deplete asparagine, an essential amino acid required by certain types of leukemia cells for protein synthesis and survival. Despite its efficacy in enhancing disease remission rate and prolonging complete remission duration in ALL patients, ASNase therapy is nevertheless confounded by a number of serious toxic effects, particularly to organs associated with high protein production (e.g., liver, pancreas), due to the systemic depletion of asparagine. Presented herein is a modified version of our previously established ATTEMPTS protein delivery system that carries the potential to permit a tumor specific, intracellular delivery of ASNase, thereby allowing for a significant reduction of ASNase-induced systemic toxicity. In a previous paper, we already demonstrated the in vitro feasibility of this heparin/protamine-regulated, TAT-mediated system in delivering ASNase directly into ASNase-sensitive murine lymphoma cells. In this article, we further validated the in vivo applicability of this system in animals harboring ASNase-encapsulated L5178Y lymphoma cells. Preliminary results showed that animals inoculated with L5178Y cells containing TAT-ASNase exhibited an extended survival rate of approximately 13% over those harboring L5178Y cells without the encapsulation of ASNase. Furthermore, the TAT-ASNase-treated mice also displayed a significantly improved hematological and liver histological status than the control groups. These findings bring promise to the use of the modified ATTEMPTS delivery system in achieving enhanced ASNase therapy.
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PMID:Preliminary in vivo evaluation of the protein transduction domain-modified ATTEMPTS approach in enhancing asparaginase therapy. 1881 76

Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-gamma, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-beta (beta isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target.
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PMID:STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma. 1942 Dec 30

A panic value is defined as an abnormal value indicating a life-threatening situation. Hematological examination results are sensitive to changes in treatment, and are likely to be influenced by blood collection techniques. Panic values may directly influence the diagnosis in many cases because they are treated as clinical evidence. Therefore, the reported results should be carefully evaluated considering the pathologic condition of the patient. In our institution, panic values are determined based on the following concept: "Panic values are established to determine when to ask the opinion of the physician in charge of the patient regarding the validity or confirmation of the clinical condition when an abnormal value is observed." This report describes our approaches for the utilization of panic values and associated problems. Values were determined by referring to those reported previously in the literature and considering differences between the former panic values and clinical conditions and the prescription history of the patients. The reports were made to the doctors in charge in each of the departments directly by telephone or pager. Clinical technologists obtained clinical information, such as on the diagnosis, infusion solutions, and medications, and asked for approval to conduct additional examinations accordingly. The numbers of reports on each item for six months from March to August in 2008 were summed. As the results, a total of four items (SFMC + TAT + D-d + FDP) accounted for 28%, hemoglobin 15%, platelets 10%, INR 9%, APTT 8%, two or more items of CBC 8%, PT+APTT 7%, differential WBC 6%, CBC + differential WBC 5%, WBC 3%, fibrinogen 0.9%, and AT 0.1%. The number of reports as a percentage of the total orders was 0.14% for CBC-related and 0.49% for hemostasis-related items. Regarding diseases and clinical conditions, blood collection-related events accounted for 11.9%, poor management of warfarin administration 9.3%, leukemia and malignant lymphoma 7.7% and chemotherapy 7.4%, and then under-administration of heparin, DIC, the perinatal period, gastrointestinal hemorrhage, severe hepatic disorder, EBV, and acute virus infection, in order of decreasing frequency. This method enabled the quick and accurate reporting of panic values to clinical sites. Furthermore, clinical technologists could be motivated to increase their awareness of the value of examinations, medications, and treatments and to be more involved in medical practice. However, there were some problems, such as intervening in the clinical practice of physicians in charge, individual variations in the performance level of clinical technologists, and insufficient uniformity of management and calculation of panic values. The provision of clinically useful information will be made possible by constructing systems to send panic values to the mobile terminals of physicians in charge and being able to refer to the results and manage medical records on the system when electronic medical charts begin to be used next year.
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PMID:[Utilization of panic values in our institution: hematological testing]. 1970 36

The lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) requires sustained extracellular signal-regulated kinase (ERK)-p90 ribosomal S6 kinase (RSK) activation, which is induced by an immediate early (IE) gene-encoded tegument protein called ORF45, to promote the late transcription and translation of viral lytic genes. An ORF45-null or single-point F66A mutation in ORF45 abolishes ORF45-RSK interaction and sustained ERK-RSK activation during lytic reactivation and subsequently results in a significant decrease in late lytic gene expression and virion production, indicating that ORF45-mediated RSK activation plays a critical role in KSHV lytic replication. Here, we demonstrate that a short ORF45-derived peptide in the RSK-binding region is sufficient for disrupting ORF45-RSK interaction, consequently suppressing lytic gene expression and virion production. We designed a nontoxic cell-permeable peptide derived from ORF45, TAT-10F10, which is composed of the ORF45 56 to 76 amino acid (aa) region and the HIV Tat protein transduction domain, and this peptide markedly inhibits KSHV lytic replication in iSLK.219 and BCBL1 cells. Importantly, this peptide enhances the inhibitory effect of rapamycin on KSHV-infected cells and decreases spontaneous and hypoxia-induced lytic replication in KSHV-positive lymphoma cells. These findings suggest that a small peptide that disrupts ORF45-RSK interaction might be a promising agent for controlling KSHV lytic infection and pathogenesis.IMPORTANCE ORF45-induced RSK activation plays an essential role in KSHV lytic replication, and ORF45-null or ORF45 F66A mutagenesis that abolishes sustained RSK activation and RSK inhibitors significantly decreases lytic replication, indicating that the ORF45-RSK association is a unique target for KSHV-related diseases. However, the side effects, low affinity, and poor efficacy of RSK modulators limit their clinical application. In this study, we developed a nontoxic cell-permeable ORF45-derived peptide from the RSK-binding region to disrupt ORF45-RSK associations and block ORF45-induced RSK activation without interfering with S6K1 activation. This peptide effectively suppresses spontaneous, hypoxia-induced, or chemically induced KSHV lytic replication and enhances the inhibitory effect of rapamycin on lytic replication and sensitivity to rapamycin in lytic KSHV-infected cells. Our results reveal that the ORF45-RSK signaling axis and KSHV lytic replication can be effectively targeted by a short peptide and provide a specific approach for treating KSHV lytic and persistent infection.
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PMID:Development of an ORF45-Derived Peptide To Inhibit the Sustained RSK Activation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus. 3084 27

Cell-based immunotherapy for the treatment of hematologic malignancies, such as leukemia and lymphoma, has seen much success and played an increasingly important role in clinical studies. Nevertheless, the efficacy of immunotherapy in solid tumors still needs improvements due to the immunosuppressive properties of tumor cells and the microenvironment. To overcome these limitations, we prepared a novel tumor-targeting delivery system based on the underlying mechanism of immune-targeted cell death that encapsulated granzyme B protein within a porous polymeric nanocapsule. Methods: A cell-penetrating peptide TAT was attached onto granzyme B (GrB) to enhance its transmembrane transport efficiency and potency to induce cell apoptosis. The endocytosis and internalization pathways of GrB-TAT (GrB-T) were analyzed in comparison with perforin by confocal microscopy and flow cytometry. Furthermore, the positively charged GrB-T was wrapped into nanoparticles by p-2-methacryloyloxy ethyl phosphorylcholine (PMPC)-modified HA (hyaluronic acid). The nanoparticles (called TCiGNPs) were characterized in terms of zeta potential and by transmission electron microscopy (TEM). The in vitro anti-tumor effects of GrB-T were examined by cell apoptosis assay and Western blotting analysis. The in vivo anti-tumor therapeutic efficacy of TCiGNPs was evaluated in a mouse tumor model. Results: The TAT peptide could play a role similar to perforin to mediate direct transmembrane transfer of GrB and improve GrB-induced cell apoptosis. The TCiGNPs were successfully synthesized and accumulated in the solid tumor through enhanced permeability and retention (EPR) effect. In the tumor microenvironment, TCiGNPs could be degraded by hyaluronidase and triggered the release of GrB-T. The TAT peptide enabled the translocation of GrB across the plasma membrane to induce tumor cell apoptosis in vivo. Conclusion: We successfully developed a granzyme B delivery system with a GrB-T core and a PMPC/HA shell that simulated CTL/NK cell-mediated cancer immunotherapy mechanism. The GrB delivery system holds great promise for cancer treatment analogous to the CTL/NK cell-induced immunotherapy.
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PMID:A novel Granzyme B nanoparticle delivery system simulates immune cell functions for suppression of solid tumors. 3169 90