Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies from this and other laboratories indicated that the oestrogen-regulated heat shock protein HSP27 is involved in the control of MCF-7 cells growth and differentiation, as it also appears to be in other cell types, including osteoblasts and HL-60 cells. In the latter instance, induction of differentiation is associated with the downregulation of myeloblastin, a serine protease now identified as proteinase 3 (hence its designation as PR3/Mbn), mirrored by an increase in the cellular content of the small heat shock protein HSP27, a substrate to this enzyme. Besides, antisense inhibition of PR3/Mbn production sufficed for inducing HL-60 cells monocytic differentiation. This prompted us to examine the hypothesis that a post-translational control on HSP27 levels (and by this on differentiation) by a serine protease might also be operating in human mammary tumour cells. As part of our attempt to evaluate this hypothesis, the present work consisted of testing the effects of a treatment of MCF-7 cells with the serine protease inhibitor N-tosyl-L-phenylalanine-chloromethyl ketone (TPCK). Our data show that this resulted in a four-fold increase in HSP27 content, associated with a 2.5-fold decrease in growth rate, the formation of cytoplasmic vesicles and increased secretion of 52 kDa peptides, identified by Western immunoblot as the isoforms of the oestrogen-regulated protein, cathepsin D. TPCK only affected growth in MDAMB-231 cells (in which HSP27 levels are very low and remained below MCF-7 cells basal levels after treatment) and failed to affect L929 cells, in which the hsp27 gene is silent. This provides circumstantial support for the assumption that effects of TPCK on the MCF-7 cells phenotype are linked to the associated increase in HSP27 content. Our recent demonstration that MCF-7 cells do in fact express PR3/Mbn fits with our concept and opens the way to test it directly, using antisense strategy.
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PMID:Effect of the serine protease inhibitor N-tosyl-l-phenylalanine-chloromethyl ketone (TPCK) on MCF-7 mammary tumour cells growth and differentiation. 1077 76

There is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan-LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan-LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.
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PMID:LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline. 1954 65

Neutrophils constitute a crucial component of the innate immune defenses against microbes. Produced in the bone marrow and patrolling in blood vessels, neutrophils are recruited to injured tissues and are immediately active to contain pathogen invasion. Neutrophils undergo programmed cell death by multiple, context-specific pathways, which have consequences on immunopathology and disease outcome. Studies in the last decade indicate additional functions for neutrophils - or a subset of neutrophils - in modulating adaptive responses and tumor progression. Neutrophil granules contain abundant amounts of various proteases, which are directly implicated in protective and pathogenic functions of neutrophils. It now emerges that neutral serine proteases such as cathepsin G and proteinase-3 also contribute to the neutrophil life cycle, but do so via different pathways than that of the aspartate protease cathepsin D and that of mutants of the serine protease elastase. The aim of this review is to appraise the present knowledge of the function of neutrophil granule proteases and their inhibitors in neutrophil cell death, and to integrate these findings in the current understandings of neutrophil life cycle and programmed cell death pathways.
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PMID:Role of granule proteases in the life and death of neutrophils. 2821 34