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)

We have reported previously that HIV-TAT-dominant negative (dn) Ras inhibits eosinophil adhesion to ICAM-1 after activation by IL-5 and eotaxin. In this study, we evaluated the role of Ras in Ag-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of dnRas, which was fused to an HIV-TAT protein transduction domain (TAT-dnRas). Uptake of TAT-dnRas (t(1/2) = 12 h) was demonstrated in leukocytes after i.p. administration. OVA-sensitization significantly increased eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid 24 h after final challenge. Treatment of animals with 3-10 mg/kg TAT-dnRas blocked the migration of eosinophils from 464 +/- 91 x 10(3)/ml to 288 +/- 79 x 10(3)/ml with 3 mg/kg of TAT-dnRas (p < 0.05), and further decreased to 116 +/- 63 x 10(3)/ml after 10 mg/kg TAT-dnRas (p < 0.01). Histological examination demonstrated that inflammatory cell infiltration (largely eosinophils and mononuclear cells) and mucin production around the airways caused by OVA were blocked by TAT-dnRas. OVA challenge also caused airway hyperresponsiveness to methacholine, which was dose dependently blocked by treatment with TAT-dnRas. TAT-dnRas also blocked Ag-induced IL-4 and IL-5, but not IFN-gamma, production in lung tissue. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by pretreatment with TAT-dnRas. By contrast, TAT-green fluorescent protein or dnRas lacking the TAT protein transduction domain did not block airway inflammation, cytokine production, or airway hyperresponsiveness. We conclude that Ras mediates Th2 cytokine production, airway inflammation, and airway hyperresponsiveness in immune-sensitized mice.
 ...
PMID:Blockade of airway inflammation and hyperresponsiveness by HIV-TAT-dominant negative Ras. 1453 Mar 63

Carcinoembryonic antigen (CEA) is expressed on human colon carcinomas, is well characterized, and continues to be a promising target for cancer immunotherapy in humans. To enhance the immunogenecity of CEA, we developed a fusion gene (CRT-TAT-DeltaCEA) of the TAT protein transduction domain (PTD) and calreticulin (CRT) with human CEA devoid of its signal sequences (DeltaCEA) and evaluated anti-tumor immunity using RNA-pulsed dendritic cell (DC) vaccination. Mice vaccinated with DC by electroporation with mRNA encoding TAT-DeltaCEA (DC/TAT-DeltaCEA) and CRT-DeltaCEA (DC/CRT-DeltaCEA) had enhanced induction of tumor-specific cytotoxic T lymphocyte (CTL) and increased numbers of IFN-gamma-secreting T cells by ELISPOT, as compared to mice vaccinated with DC/DeltaCEA. DC/CRT-DeltaCEA and DC/TAT-DeltaCEA vaccines preferentially stimulated CD4+ and CD8+ T cells, respectively. The DC vaccine by electroporation with mRNA encoding CRT-TAT-DeltaCEA (DC/CRT-TAT-DeltaCEA) enhanced both CD4+ and CD8+ T cells. DC/CRT-TAT-DeltaCEA had the additional effects of CRT and TAT PTD and enhanced the anti-tumor effect against CEA-expressing tumors compared to DC/CRT-DeltaCEA or DC/TAT-DeltaCEA. These findings suggest that modification of CEA with both CRT and TAT PTD induces potent anti-tumor immune responses in RNA-pulsed DC vaccination and may be a useful approach for DC-based immunotherapy.
 ...
PMID:Modification of CEA with both CRT and TAT PTD induces potent anti-tumor immune responses in RNA-pulsed DC vaccination. 1881 1

Although JNK is a potential target for treating chronic inflammatory diseases, its role in T lymphocyte function remains controversial. To overcome some of the previous limitations in addressing this issue we have used the recently described transactivator of transcription-JNK-interacting protein (TAT-JIP) peptide, a specific inhibitor that was derived from the minimal JNK-binding region of the scaffold protein, JNK-interacting protein 1 (JIP-1), coupled to the short cell-permeable HIV TAT sequence. Pretreatment of purified human T lymphocytes with the TAT-JIP peptide inhibited the phosphorylation of endogenous jun activated by PHA-PMA. This was associated with a corresponding inhibition of lymphoproliferation, and of IL-2, IFN-gamma, lymphotoxin, and IL-10 cytokine production. Similar results were also found using mouse splenic T cells. Examination of the specificity of TAT-JIP revealed that although the peptide was more selective than the pharmacological inhibitor, SP600125, it also inhibited cyclin-dependent kinase 2, p70 ribosomal protein S6 kinase, and serum and glucocorticoid-regulated kinase activity. Nevertheless, these data demonstrate for the first time the ability of the TAT-JIP peptide to inhibit the JNK pathway and the phosphorylation of jun in intact cells, thereby preventing the activation of the transcription factor, AP-1, and the production of Th1 and Th2 cytokines. Thus JNK could potentially be a target for the development of drugs for the treatment of autoimmune inflammatory diseases.
 ...
PMID:The effect of the JNK inhibitor, JIP peptide, on human T lymphocyte proliferation and cytokine production. 1898 Nov 52

Immunity to the bovine apicomplexan parasite Theileria parva is associated with MHC-I restricted CD8+ T cell responses directed against the intralymphocytic schizont stage of the parasite. A number of schizont-stage antigens that are targets of CD8+ T cell responses from immune animals have been identified but an effective delivery strategy that consistently induces protective CD8+ T cell responses remains to be developed. This study aimed to determine whether fusing Tat, a cell penetrating peptide (CPP) from HIV-1 TAT, to a CD8+ T cell target antigen from T. parva (Tp2) enhances the cytosolic delivery and subsequent stimulation of bovine CD8+ T cell responses in vitro. Using IFN-gamma ELISpot and cytotoxicity assays, it was demonstrated that recombinant Tat-Tp2 fusion protein possessed a superior ability to access MHC-I processing and presentation pathway and to stimulate CD8+ T cell responses compared to recombinant Tp2 protein. Exposure of APC to Tat-Tp2 protein for only 30 min was sufficient for protein uptake and stimulation of CD8+ T cells. This work describes for the first time the utility of a CPP to enhance MHC-I presentation in a veterinary species and supports the evaluation of CPP fusion proteins in the induction of CD8+ T cell responses in vivo.
 ...
PMID:Fusion of a cell penetrating peptide from HIV-1 TAT to the Theileria parva antigen Tp2 enhances the stimulation of bovine CD8+ T cell responses. 1924 7

Because multiple tumor antigens, including carcinoembryonic antigen (CEA) and survivin (SVV), have been frequently observed in human colorectal cancer, we investigated whether the expression of both CEA and SVV by co-transduction of adenovirus vectors into dendritic cells (DCs) could improve anti-tumor immunity in a murine colorectal cancer model. The adaptor fusion protein of Coxsackie and adenovirus receptor and TAT-protein transduction domain (CAR-TAT) enhanced co-transduction of adenovirus vectors encoding CEA (AdCEA) and SVV (AdSVV) into DCs, and increased anti-tumor immunity. DCs expressing both CEA and SVV in the presence of CAR-TAT (DC-AdCEA/AdSVV+CAR-TAT) induced T-cell responses specific for CEA and SVV, and enhanced cytotoxic T-cell activity on MC38/CEA2 cells expressing CEA and SVV compared with DCs expressing either CEA or SVV alone. Particularly, DC-AdCEA/AdSVV+CAR-TAT induced higher number of CEA-specific IFN-gamma secreting T cells compared with DC-AdCEA+CAR-TAT. Vaccination with DC-AdCEA/AdSVV+CAR-TAT also more efficiently inhibited tumor growth compared with DCs expressing either CEA or SVV alone in therapeutic tumor models. These results suggest that efficient co-transduction of multiple adenovirus vectors by CAR-TAT could be used to develop various strategies for therapeutic DC vaccines.
 ...
PMID:Efficient co-transduction of adenoviral vectors encoding carcinoembryonic antigen and survivin into dendritic cells by the CAR-TAT adaptor molecule enhance anti-tumor immunity in a murine colorectal cancer model. 2021 Dec 3