Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthetic peptides with the arginine-glycine-aspartate (RGD) motif have been used widely as inhibitors of integrin-ligand interactions to study cell growth, adhesion, migration and differentiation. We designed cyclic-RGD peptide (Tpa-RGDWPC-, cRGD) which could cause cell death in MCF-7 cell line. In order to understand the mechanism involved in cRGD-induced apoptosis, we used microarray, real-time quantitative PCR (Q-PCR) and bioinformatics to study the effects of cRGD on breast cancer cell line MCF-7. By time-series gene expression measurements and our developed software BSIP and GeneNetwork, we reconstructed an apoptosis-related gene network. In the network, caspase-9, located at the upstream, activates downstream effector caspases such as caspase-7, leading to the induction of caspase-4. Combined our previous proteomics data with newly performed docking simulation, it indicated that the cell death induced by cRGD may be triggered through blocking integrin signaling to the extracellular matrix and activation of caspase pathway. This study provides a molecular explanation of cRGD treatment in breast cancer cells and set forth a constructive far-reaching impact on breast cancer therapy.
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PMID:An apoptosis-related gene network induced by novel compound-cRGD in human breast cancer cells. 1762 35

Apoptotic caspases, such as caspase-7, are stored as inactive protease zymogens, and when activated, lead to a fate-determining switch to induce cell death. We previously discovered small molecule thiol-containing inhibitors that when tethered revealed an allosteric site and trapped a conformation similar to the zymogen form of the enzyme. We noted three structural transitions that the compounds induced: (i) breaking of an interaction between Tyr-223 and Arg-187 in the allosteric site, which prevents proper ordering of the catalytic cysteine; (ii) pinning the L2' loop over the allosteric site, which blocks critical interactions for proper ordering of the substrate-binding groove; and (iii) a hinge-like rotation at Gly-188 positioned after the catalytic Cys-186 and Arg-187. Here we report a systematic mutational analysis of these regions to dissect their functional importance to mediate the allosteric transition induced by these compounds. Mutating the hinge Gly-188 to the restrictive proline causes a massive approximately 6000-fold reduction in catalytic efficiency. Mutations in the Arg-187-Tyr-223 couple have a far less dramatic effect (3-20-fold reductions). Interestingly, although the allosteric couple mutants still allow binding and allosteric inhibition, they partially relieve the mutual exclusivity of binding between inhibitors at the active and allosteric sites. These data highlight a small set of residues critical for mediating the transition from active to inactive zymogen-like states.
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PMID:Dissecting an allosteric switch in caspase-7 using chemical and mutational probes. 1958 39

Arginine deprivation achieved by means of recombinant arginine-degrading enzymes is currently being developed as a novel anticancer enzymotherapy. In this study, we showed that arginine deprivation in vitro profoundly and selectively sensitized human cancer cells of different organ origin to low doses of canavanine, an arginine analogue of plant origin. In sensitive cancer cells arginine starvation led to the activation of caspase-9, caspase-3 and caspase-7, cleavage of reparation enzyme, polyADP ribosyl polymerase, and DNA fragmentation, which are the typical hallmarks of intrinsic apoptosis realized by the mitochondrial pathway. Co-administration of canavanine significantly accelerated and enhanced apoptotic manifestations induced by arginine deprivation. The augmentation of canavanine toxicity for cancer cells was observed when either a formulated arginine-free medium or complete medium supplemented with bovine arginase preparation was used. Cycloheximide efficiently rescued malignant cells from canavanine-induced cytotoxicity under arginine deprivation, suggesting that it results mainly from canavanine incorporation into newly synthesized proteins. Cancer cells sensitive or resistant to arginine deprivation alone were not capable of restoring their proliferation after 24 h of combined treatment, whereas pseudonormal cells retained such ability. Our data suggest that the incorporation of canavanine into anticancer treatment schemes based on artificially created arginine starvation could be a novel strategy in tumor enzymochemotherapy.
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PMID:Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells. 2071 4

Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.
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PMID:A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17. 2874 58

The objective of this study was to synthesize and characterize novel polyurethane (PU)-nanofiber coated with l-arginine by electrospinning technique. This study determined whether l-arginine conjugated with PU-nanofiber could stimulate cell proliferation and prevent H2O2-induced cell death in satellite cells co-cultured with fibroblasts isolated from Hanwoo (Korean native cattle). Our results showed that l-arginine conjugated with PU nanofiber could reduce cytotoxicity of co-cultured satellite cells. Protein expression levels of bcl-2 were significantly upregulated whereas those of caspase-3 and caspase-7 were significantly downregulated in co-culture of satellite cells compared to those of monoculture cells after treatment with PU-nanofiber coated with l-arginine and which confirmed by Confocal microscope. These results suggest that co-culture of satellite cells with fibroblasts might be able to counter oxidative stress through translocation/penetration of antioxidant, collagen, and molecules secreted to satellite cells. Therefore, this nanofiber might be useful as a wound dressing in animals to counter oxidative stresses.
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PMID:Fabrication of nanofiber coated with l-arginine via electrospinning technique: a novel nanomatrix to counter oxidative stress under crosstalk of co-cultured fibroblasts and satellite cells. 3018 42