Disease relevance of Cts7-ps

• When mice were injected intravenously with the cathepsin reporter probe, intestinal adenomas became highly fluorescent indicative of high cathepsin B enzyme activity [1].
• Using gene expression profiling, we identified cathepsin cysteine proteases as highly up-regulated genes in a mouse model of human lung adenocarcinoma [2].
• This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM) [3].
• Cathepsin protease activity modulates amyloid load in extracerebral amyloidosis [4].
• These data suggest that cathepsin-mediated cleavage could prime AAV capsids for subsequent nuclear uncoating, and indicate that analysis of additional genes recovered in our screen may help to further elucidate the mechanisms behind transduction by AAV8 and related serotypes.Molecular Therapy (2007) 15, 330-339. doi:10.1038/sj.mt.6300053 [5].

High impact information on Cts7-ps

• IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities [6].
• We show that the defect in positive selection in the cathepsin L-/- thymus is specific for CD4+ T cells that can be selected in a wild-type and provide evidence that the repertoire of T cells selected differs from that in wild-type mice, suggesting cortical thymic epithelial cells in cathepsin L knockout mice express an altered peptide repertoire [7].
• Cathepsin (Cat) S and L are the major elastinolytic cysteine proteases in mouse macrophages [8].
• We show that CTL and NK cells die within a few hours if they are triggered to degranulate in the presence of nontoxic thiol cathepsin protease inhibitors [9].
• Immunolabeling demonstrated a rearrangement of the endocytic system and a redistribution of extracellularly located enzymes in thyroids of cathepsin-deficient mice [10].

Chemical compound and disease context of Cts7-ps

• In vitro, brusatol and bruceoside A marginally inhibited 10-day P-388 lymphocytic leukemia DNA polymerase, RNA polymerase, thymidylate synthetase, dihydrofolate reductase, phosphoribosyl pyrophosphate aminotransferase, and cathepsin protease activities [11].
• Cathepsin inhibition was investigated in the dextran-sulphate-sodium (DSS) colitis model in mice with application of pepstatin A (CTSD inhibitor), CA-074 (CTSB inhibitor) and Z-Phe-Tyr-aldehyde (CTSL inhibitor) [12].
• Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion [13].

Biological context of Cts7-ps

• We conclude that neither Cat B nor Cat D are essential for MHC class II-mediated antigen presentation [14].
• JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways [15].
• With the regression of the decidua beginning on day 9.5, a coordinated upregulation of both cathepsin B and cystatin C was observed implying a role for controlled cathepsin expression during apoptosis [16].
• Apoptosis was reduced in the presence of cathepsin inhibitors, suggesting the involvement of lysosomal proteases in this novel death response [17].
• Latex bead-exposed PEC were not more potent APC, and their thiol cathepsin activities were unchanged, indicating that phagocytosis and nonspecific irritation were not responsible [18].

Anatomical context of Cts7-ps

• Although the absence of these proteases provoked a modest shift in the efficiency of presentation of some antigenic determinants, the overall capacity of Cat B-/- or Cat D-/- antigen-presenting cells was unaffected [14].
• Certain tumor cell lines directly stimulate platelet activity, some by releasing platelet-aggregating material, a urea-extractable membrane component, others by release of cathepsin, and still others by undefined mechanisms [19].
• Because an acidic pericellular pH has been shown to induce translocation of lysosomes in macrophages and fibroblasts, we evaluated the intracellular distribution of cathepsin B+ vesicles and secretion of cathepsin B in cell pairs incubated at slightly acidic pH [20].
• Substrate gel electrophoresis showed an increase in giant cell cathepsin activity with enzyme profiles changing at the end of the invasive period [16].
• Both the redistribution of cathepsin B+ vesicles toward the cell surface induced by acidic pH and the constitutive and acidic pH-induced secretion of active cathepsin B could be inhibited by microtubule poisons and stabilizers [20].

Associations of Cts7-ps with chemical compounds

• Cathepsin K(-/-)/L(-/-) mice had significantly reduced levels of free thyroxine, indicating that utilization of luminal thyroglobulin for thyroxine liberation is mediated by a combinatory action of cathepsins K and L [10].
• This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors [21].
• Instead, cathepsin (Cat) G, a serine protease that is not endogenously synthesized by B lymphocytes, is internalized from the plasma membrane and present in lysosomes from human B cells where it represents a major functional constituent of the proteolytic machinery [22].
• Gallium arsenide modulates proteolytic cathepsin activities and antigen processing by macrophages [18].
• RESULTS: The pharmacokinetic behavior of the cathepsin-degradable peptide-linked RICs was similar to that for the 2-iminothiolane (2IT) nondegradable linked RICs except for the liver [23].

Physical interactions of Cts7-ps

• Loading of antigenic peptide fragments on major histocompatibility complex class II molecules is essential for generation of CD4(+) T cell responses and occurs after cathepsin-mediated degradation of the invariant chain chaperone molecule [24].

Regulatory relationships of Cts7-ps

• RANK ligand and interferon gamma differentially regulate cathepsin gene expression in pre-osteoclastic cells [25].

Other interactions of Cts7-ps

• Mixed lysates of L cells and LX cells lack activity of both cathepsin B and cathepsin L, suggesting the presence of an inhibitor of cathepsin function in LX cells [26].
• Furthermore, cathepsin expression was similar to the expression of the macrophage marker macrosialin (CD68) although expression of cathepsins B, D, and L could be demonstrated in healthy C57BL/6 mice and in nonaffected vessel segments of atherosclerotic ApoE-/- mice [27].
• Cycloheximide treatment of peritoneal macrophages inhibited the increase in cathepsin H mRNA levels induced by IFN-gamma, suggesting that the increase in cathepsin mRNA levels requires de novo protein synthesis [28].
• Proinsulin/insulin is synthesized locally and prevents caspase- and cathepsin-mediated cell death in the embryonic mouse retina [29].
• Treatment of cells in vivo with two cell permeant peptide fluoromethylketone inhibitors of caspase activity, Z-VAD-fmk and Z-DEVD-fmk, inhibited DX- and TG-induced apoptotic nuclear changes and maintained plasma membrane integrity, whereas the cathepsin inhibitor, Z-FA-fmk, and two calpain inhibitors failed to inhibit apoptosis [30].

Analytical, diagnostic and therapeutic context of Cts7-ps

• Overexpression of cathepsin proteases in these lung tumors was confirmed by immunohistochemistry and Western blotting [2].
• However, activity of cathepsin B-GFP expressed in LX cells can be recovered by incubating the immunoprecipitate with L cell lysate followed by immunoprecipitation, providing further evidence that LX cells express a cathepsin inhibitor [26].
• In double label immunofluorescence studies, cathepsin E co-localized with cathepsin D-myc-KDEL, an endoplasmic reticulum (ER) marker [31].
• CONCLUSIONS: Cathepsin-degradable peptides used to link chelated radiometals to antibodies reduce liver radiation dose and improve the therapeutic index for radioimmunotherapy given in combination with bone marrow support [23].
• Cumulated activities of peptide-linked RICs in the xenografts were as great as those of 2IT RICs, so that the therapeutic indices (tumor: liver cumulated activity ratios) were substantially better for cathepsin-degradable peptide-linked RICs [23].

References