Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel member of the tumor necrosis factor (TNF) receptor family, designated TRAMP, has been identified. The structural organization of the 393 amino acid long human TRAMP is most homologous to TNF receptor 1. TRAMP is abundantly expressed on thymocytes and lymphocytes. Its extracellular domain is composed of four cysteine-rich domains, and the cytoplasmic region contains a death domain known to signal apoptosis. Overexpression of TRAMP leads to two major responses, NF-kappaB activation and apoptosis. TRAMP-induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl-2. In addition, TRAMP does not appear to interact with any of the known apoptosis-inducing ligands of the TNF family.
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PMID:TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). 905 39

We have identified and characterized ARC, apoptosis repressor with caspase recruitment domain (CARD). Sequence analysis revealed that ARC contains an N-terminal CARD fused to a C-terminal region rich in proline/glutamic acid residues. The CARD domain of ARC exhibited significant homology to the prodomains of apical caspases and the CARDs present in the cell death regulators Apaf-1 and RAIDD. Immunoprecipitation analysis revealed that ARC interacts with caspase-2, -8, and Caenorhabditis elegans CED-3, but not with caspase-1, -3, or -9. ARC inhibited apoptosis induced by caspase-8 and CED-3 but not that mediated by caspase-9. Further analysis showed that the enzymatic activity of caspase-8 was inhibited by ARC in 293T cells. Consistent with the inhibition of caspase-8, ARC attenuated apoptosis induced by FADD and TRADD and that triggered by stimulation of death receptors coupled to caspase-8, including CD95/Fas, tumor necrosis factor-R1, and TRAMP/DR3. Remarkably, the expression of human ARC was primarily restricted to skeletal muscle and cardiac tissue. Thus, ARC represents an inhibitor of apoptosis expressed in muscle that appears to selectively target caspases. Delivery of ARC by gene transfer or enhancement of its endogenous activity may provide a strategy for the treatment of diseases that are characterized by inappropriately increased cell death in muscle tissue.
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PMID:ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. 956 Feb 45

In patients with localized prostate cancer, radical prostatectomy and radiation therapy, although effective in controlling localized disease, are often associated with significant side effects attributable to injury of adjacent tissues. Moreover, patients with metastatic disease eventually fail systemic hormonal or chemotherapy because of the development of progressive, refractory disease. In this study, we evaluated the safety and efficacy of a novel suicide gene therapy that could potentially spare normal tissue while bypassing molecular mechanisms of apoptosis resistance by using chemically inducible effector caspases to trigger apoptosis in prostate cancer cells. Initially, we compared the ability of a panel of inducible Fas signaling intermediates to kill human and murine prostate cancer cell lines. On the basis of the superior killing by downstream caspase-1 and caspase-3, replication-deficient adenoviral vectors expressing conditional caspase-1 (Ad-G/iCasp1) or caspase-3 (Ad-G/iCasp3), regulated by nontoxic, lipid-permeable, chemical inducers of dimerization (CID), were constructed. Upon vector transduction followed by CID administration, aggregation and activation of these recombinant caspases occur, leading to rapid apoptosis. In vitro, both human (LNCaP and PC-3) and murine (TRAMP-C2 and TRAMP-C2G) prostate cancer cell lines were efficiently transduced and killed in a CID-dependent fashion. In vivo, direct injection of Ad-G/iCasp1 into s.c. TRAMP-C2 tumors caused focal but extensive apoptosis without evidence for a bystander effect at the maximal viral dose (i.e., 2.5 x 10(10) viral particles/25 microl) in host animals that also received CID compared with control animals. Treatment with Ad-G/iCasp1 plus CID resulted in a transient, yet significant, reduction both in tumor growth and volume compared with tumors treated with vector but not CID (P < 0.035) or vector-diluent plus CID (P < 0.022), both of which grew more rapidly. These results demonstrate that CID-regulated, caspase-based suicide gene therapy is safe and can inhibit the growth of experimental prostate cancer in vitro and in vivo through potent induction of apoptosis, providing a rationale for further development.
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PMID:Adenovirus-mediated transfer of inducible caspases: a novel "death switch" gene therapeutic approach to prostate cancer. 1128 32