Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stefin B (cystatin B) is an inhibitor of lysosomal cysteine cathepsins and does not inhibit cathepsin D, E (aspartic) or cathepsin G (serine) proteinases. In this study, we have investigated apoptosis triggered by camptothecin, staurosporin (STS), and anti-CD95 monoclonal antibody in the thymocytes from the stefin B-deficient mice and wild-type mice. We have observed increased sensibility to STS-induced apoptosis in the thymocytes of stefin B-deficient mice. Pretreatment of cells with pan-caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone completely inhibited phosphatidylserine externalization and caspase activation, while treatment with inhibitor of calpains- and papain-like cathepsins (2S,3S)-trans-epoxysuccinyl-leucylamido-3-methyl-butane ethyl ester did not prevent caspase activation nor phosphatidylserine exposure. We conclude that sensitization to apoptosis induced by STS in thymocytes of stefin B-deficient and wild-type mice is not dependent on cathepsin inhibition by stefin B.
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PMID:Sensitization of stefin B-deficient thymocytes towards staurosporin-induced apoptosis is independent of cysteine cathepsins. 1581 33

Proteolytic processes are necessary for normal physiological functions in the body. Failure in the biological control mechanisms of proteolytic activities may cause various diseases, for example, it may enable tumor invasion and metastasis. In the metastatic process, proteolytic enzymes play an important role in mediating passage of the malignant cell through the cell membrane. Tumor cell migration and invasion into the surrounding extracellular matrix is facilitated by a variety of cell surface-associated proteolytic enzymes: matrix metalloproteinases (MMPs), cysteine proteases including cathepsins B and L, aspartic protease cathepsin D, and serine proteases including plasmin and urokinase plasminogen activator (uPA). Many of the natural and synthetic inhibitors of the proteases prevent the dissemination of cancer cells and have also inhibitory effect on tumor growth. Thus inhibition of protease activity by low molecular weight inhibitors represents a promising strategy for anticancer and antimetastatic therapy. The review surveys low molecular inhibitors of MMPs, uPA and lysosomal proteases.
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PMID:Inhibitors of proteases as anticancer drugs. 1587 78

Tripeptidyl-peptidase I (TPPI) is an acidic lysosomal peptidase that removes tripeptides from an unmodified N-terminus of small proteins and polypeptides. In humans, TPP I constitutes an integral part of the lysosomal proteolytic apparatus, which, includes numerous hydrolytic enzymes, mostly cysteine proteases (cathepsin B, C, H, K, L, and others), but also serine (cathepsin A) and aspartic (cathepsin D) proteases. The combination of endo- and exopeptidase activities of these enzymes allows for efficient digestion of the diverse proteins transported to the lysosomes, releasing free amino acids and dipeptides that are transported back to the cytoplasm and reused according to the metabolic needs of the cell. The role of TPP I in normal lysosome functioning is underscored by the genetic association of the enzyme with one form of a group of the developmental neurodegenerative disorders of childhood--the neuronal ceroid lipofuscinoses (NCLs). The scope of this article is to review the most recent data, mostly from author's laboratory, on the biology and pathology of TPP I. NCLs are also shortly reviewed with the special emphasis on CLN2 form resulting from mutations in TPP I gene.
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PMID:[Tripeptidyl-peptidase I--distribution, biogenesis, and mechanisms of activation]. 1686 97

Proteases frequently function not only as individual enzymes but also in cascades or networks. A notable evolutionary switch occurred in one such protease network that is involved in protein digestion in the intestine. In vertebrates, this is largely the work of trypsin family serine proteases, whereas in invertebrates, cysteine proteases of the papain family and aspartic proteases assume the role. Utilizing a combination of protease class-specific inhibitors and RNA interference, we deconvoluted such a network of major endopeptidases functioning in invertebrate intestinal protein digestion, using the parasitic helminth, Schistosoma mansoni as an experimental model. We show that initial degradation of host blood proteins is ordered, occasionally redundant, and substrate-specific. Although inhibition of parasite cathepsin D had a greater effect on primary cleavage of hemoglobin, inhibition of cathepsin B predominated in albumin degradation. Nevertheless, in both cases, inhibitor combinations were synergistic. An asparaginyl endopeptidase (legumain) also synergized with cathepsin B and L in protein digestion, either by zymogen activation or facilitating substrate cleavage. This protease network operates optimally in acidic pH compartments either in the gut lumen or in vacuoles of the intestinal lining cells. Defining the role of each of these major enzymes now provides a clearer understanding of the function of a complex protease network that is conserved throughout invertebrate evolution. It also provides insights into which of these proteases are logical targets for development of chemotherapy for schistosomiasis, a major global health problem.
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PMID:A multienzyme network functions in intestinal protein digestion by a platyhelminth parasite. 1702 79

Proteolytic degradation represents a significant barrier to the efficient production of several recombinant proteins in plants, both in vivo during their expression and in vitro during their recovery from source tissues. Here, we describe a strategy to protect recombinant proteins during the recovery process, based on the coexpression of a heterologous proteinase inhibitor acting as a 'mouse trap' against the host proteases during extraction. After confirming the importance of trypsin- and chymotrypsin-like activities in crude protein extracts of potato (Solanum tuberosum L.) leaves, transgenic lines of potato expressing either tomato cathepsin D inhibitor (CDI) or bovine aprotinin, both active against trypsin and chymotrypsin, were generated by Agrobacterium tumefaciens-mediated genetic transformation. Leaf crude protein extracts from CDI-expressing lines, showing decreased levels of cathepsin D-like and ribulose 1,5-bisphosphate carboxylase/oxygenase hydrolysing activities in vitro, conducted decreased turnover rates of the selection marker protein neomycin phosphotransferase II (NPTII) relative to the turnover rates measured for transgenic lines expressing only the marker protein. A similar stabilizing effect on NPTII was observed in leaf protein extracts from plant lines coexpressing bovine aprotinin, confirming the ability of ectopically expressed broad-spectrum serine proteinase inhibitors to reproduce the protein-stabilizing effect of low-molecular-weight proteinase inhibitors generally added to protein extraction media.
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PMID:An in-built proteinase inhibitor system for the protection of recombinant proteins recovered from transgenic plants. 1714 41

To control the rate of release of methylprednisolone (MP) in lysosomes, new dextran-MP conjugates with peptide linkers were synthesized and characterized. Methylprednisolone succinate (MPS) was attached to dextran 25 kDa using linkers with 1-5 Gly residues. The release characteristics of the conjugates in pH 4.0 and 7.4 buffers, blood, liver lysosomes, and various lysosomal proteinases were determined using a size-exclusion and/or a newly developed reversed-phase HPLC method capable of simultaneous quantitation of MP, MPS, and all five possible MPS-peptidyl intermediates. We synthesized conjugates with >or=90% purity and 6.9-9.5% (w/w) degree of MP substitution. The conjugates were stable at pH 4.0, but released MP and intact MPS-peptidyl intermediates in the pH 7.4 buffer and rat blood, with faster degradation rates for longer linkers. Rat lysosomal fractions degraded the conjugates to MP and all the possible intermediates also at a rate directly proportional to the length of the peptide. Whereas the degradation of the conjugates by cysteine peptidases (papain or cathepsin B) was relatively substantial, no degradation was observed in the presence of aspartic (cathepsin D) or serine (trypsin) proteinases, which do not cleave peptide bonds with Gly. These newly developed dextran conjugates of MP show promise for controlled delivery of MP in lysosomes.
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PMID:Synthesis and in vitro characterization of novel dextran-methylprednisolone conjugates with peptide linkers: effects of linker length on hydrolytic and enzymatic release of methylprednisolone and its peptidyl intermediates. 1785 26

SaPIN2a encodes a proteinase inhibitor in nightshade (Solanum americanum), which is specifically localized to the enucleate sieve elements. It has been proposed to play an important role in phloem development by regulating proteolysis in sieve elements. In this study, we purified and characterized native SaPIN2a from nightshade stems and recombinant SaPIN2a expressed in Escherichia coli. Purified native SaPIN2a was found as a charge isomer family of homodimers, and was weakly glycosylated. Native SaPIN2a significantly inhibited serine proteinases such as trypsin, chymotrypsin, and subtilisin, with the most potent inhibitory activity on subtilisin. It did not inhibit cysteine proteinase papain and aspartic proteinase cathepsin D. Recombinant SaPIN2a had a strong inhibitory effect on chymotrypsin, but its inhibitory activities toward trypsin and especially toward subtilisin were greatly reduced. In addition, native SaPIN2a can effectively inhibit midgut trypsin-like activities from Trichoplusia ni and Spodoptera litura larvae, suggesting a potential for the production of insect-resistant transgenic plants.
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PMID:Purification and characterization of native and recombinant SaPIN2a, a plant sieve element-localized proteinase inhibitor. 1787 May 92

We previously described the novel zinc finger protein ZKSCAN3 as a new "driver" of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Met-related tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin beta 4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin beta 4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin beta 4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin beta 4 promoter in vitro and in vivo, and the integrin beta 4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin beta 4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin beta 4.
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PMID:Unbiased screening for transcriptional targets of ZKSCAN3 identifies integrin beta 4 and vascular endothelial growth factor as downstream targets. 1894 Aug 3

Two aspartyl proteases activities were identified and isolated from Trypanosoma cruzi epimastigotes: cruzipsin-I (CZP-I) and cruzipsin-II (CZP-II). One was isolated from a soluble fraction (CZP-II) and the other was solubilized with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CZP-I). The molecular mass of both proteases was estimated to be 120 kDa by HPLC gel filtration and the activity of the enzymes was detected in a doublet of bands (56 and 48 kDa) by substrate-sodium dodecyl sulphate-polyacrylamide-gelatin gel electrophoresis. Substrate specificity studies indicated that the enzymes consistently hydrolyze the cathepsin D substrate Phe-Ala-Ala-Phe (4-NO2)-Phe-Val-Leu-O4MP but failed to hydrolyze serine and other protease substrates. Both proteases activities were strongly inhibited by the classic inhibitor pepstatin-A (> or =68%) and the aspartic active site labeling agent, 1,2-epoxy-3-(phenyl-nitrophenoxy) propane (> or =80%). These findings show that both proteases are novel T. cruzi acidic proteases. The physiological function of these enzymes in T. cruzi has under investigation.
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PMID:Trypanosoma cruzi: isolation and characterization of aspartyl proteases. 1921 6

Alternative splicing of precursor mRNA is a fundamental mechanism to generate multiple proteins from a single gene. Although constitutive and alternative mRNA splicing is temporally and spatially regulated, deregulation of mRNA splicing could cause development, progression, and metastasis of tumors. Through yeast two-hybrid screening of a human breast cDNA library using estrogen receptor-alpha (ERalpha) as bait, we identified a novel nuclear receptor box containing full-length protein, nuclear protein E3-3 (NPE3-3). Our results revealed that NPE3-3 associates with not only ERalpha but also with splicing factors, serine/arginine-rich protein (SRp)-30c, SRp40, and splicing factor SC-35, suggesting that NPE3-3 is likely to be involved in regulation of mRNA splicing. Accordingly, transient expression of NPE3-3 in cells resulted in expected splicing of the CD44 control minigene. We also discovered that NPE3-3-overexpressing clones produced a novel, previously unrecognized, alternatively spliced variant of ERalpha (termed ERalphaV), which had a molecular size of 37 kDa composed of only exons 1, 2, 7, and 8. ERalphaV was expressed and sequestered in the cytoplasm in MCF-7 cells stably overexpressing NPE3-3, suggesting its involvement in nongenomic hormone signaling. NPE3-3 clones exhibited up-regulation of ERK1/2 signaling, cyclin D1, and cathepsin D and enhanced tumor cell proliferation, migration, and tumorigenicity. Moreover, direct expression of the ERalphaV in breast cancer cells stimulated ERK1/2 up-regulation and cyclin D1 expression. We found that ERalphaV physically interacted with MAPK kinase (MEK)-1/2, and thus, an ERalphaV and MEK1/2 complex could lead to the activation of the ERK1/2 pathway. Interestingly, NPE3-3 was up-regulated in human breast tumors. These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERalpha is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells.
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PMID:Identification of a novel estrogen receptor-alpha variant and its upstream splicing regulator. 2030 96


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