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

---

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

The processing of antigenic peptides for presentation by MHC molecules to T cells, may depend upon the function of a second, consensus sequence in or near the T cell-presented epitope. One such processing-regulating sequence appears to be composed of amino acids Leu, Ile, Val, Phe, and Met recurring in a fashion to form a longitudinal, hydrophobic strip when the excised peptide is coiled as an alpha-helix. Such a hydrophobic strip-of-helix may: (a) scavenge peptides from lumens onto lipid membranes of digestion vesicles, (b) stabilize peptides there as protease-resistant helices, (c) specify recognition by the antigenic peptide-binding sites of chaperonin proteins, transmembranal transporters, or MHC molecules. By circular dichroism and electron paramagnetic resonance, we demonstrated that peptides with recurrent hydrophobic residues potentially forming longitudinal strips adsorbed to, and partially coiled as helices on, di-O-hexadecyl, D-L-alpha-phosphatidylcholine (DHPC) vesicles. Cathepsin B or cathepsin D cleavages of three such peptides were identified. With either enzyme, it made no significant difference whether a peptide substrate was in solution or bound to vesicles in terms of efficiency and specificity of peptide bond cleavages. We conclude that protease resistance, per se, of membrane-adsorbed, helically coiled peptides is not a major factor in the selection for T cell presentation of epitopes in peptides which have a motif with a longitudinal hydrophobic strip.
...
PMID:Adsorption and helical coiling of amphipathic peptides on lipid vesicles leads to negligible protection from cathepsin B or cathepsin D. 838 60

To elucidate involvement of proteinases in malignancy of keratinocytes, expression of cathepsin B, a cysteine proteinase, and cathepsin D, an aspartic proteinase, was ascertained in formalin-fixed paraffin-embedded specimens of normal skin, squamous cell carcinoma (SCC). Bowen's disease, seborrhoeic keratosis and basal cell carcinoma (BCC). Presence of procathepsin B and an intermediate form of cathepsin D was confirmed by Western blotting and enzyme activity analysis. Cathepsin B stained more intensely in SCC tumour cells than in normal epidermis; staining patterns were diffuse, granular or both. Diffuse and granular patterns (procathepsin B and mature enzyme, respectively) appeared in inner and outer parts of tumour islands, respectively. Five of 20 cases of Bowen's disease showed diffuse enhanced cathepsin B expression; 20 cases of seborrhoeic keratosis or BCC did not. Cathepsin D stained intensely in tumour cells of half the SCC cases. The staining manner and distribution of cathepsins B and D was similar in the cytoplasm of cancer cells. No enhanced staining of cathepsin D was seen in any cases of Bowen's disease, seborrhoeic keratosis, or BCC. Coexistence and localization of active mature forms of cathepsins B and D suggests that cooperation between the two enzymes may play an important part in invasion of SCC.
...
PMID:Cathepsin B and D expression in squamous cell carcinoma. 897 10

Proteinase activity is increased in psoriatic epidermis. To elucidate the involvement of enzymes in psoriatic epidermis, the expression of cathepsins, L, B and D was investigated by Western blotting and immunohistological studies. Normal epidermis contained abundant inactive precursors (39 kDa) of cathepsins L and B and an inactive intermediate form (45 kDa) of cathepsin D. Cathepsin L in psoriasis was processed to a variable extent from the precursor to a single-chain form (30 kDa) and a mixture of single- and heavy-chain (25 kDa) forms of the active mature enzyme, corresponding to the immunohistological staining patterns 'diffuse dense', 'small granular', and unevenly distributed 'condensed granular'. Cathepsin B showed a mixture of precursor form (39 kDa) and single-chain (30 kDa) forms and was expressed as a 'diffuse dense' staining pattern in the mid-spinous layer and as a 'condensed' pattern in the upper spinous and granular layers. Cathepsin D was processed to the heavy-chain (31 kDa) form of activated mature enzyme with small granular staining and a mixture of heavy-chain and degraded protein (28 kDa) with larger and more condensed granular staining. The distribution patterns of 'small granular' cathepsin L, and of cathepsins B and D expression in suprabasal keratinocytes were very similar to that of involucrin. After complete clinical resolution of psoriasis by 8-methoxypsoralen plus UVA treatment, the expression of the three cathepsins was normalized. These results suggest that cathepsins L, B and D in forms activated to a variable extent may be involved in the pathology of psoriasis.
...
PMID:Processing of cathepsins L, B and D in psoriatic epidermis. 904 42

To determine the involvement of proteinases with hydrolytic activity towards extracellular matrix and basement membrane, in invasion and metastasis of tumour cells, the expression of cathepsin D, an aspartic proteinase, and cathepsin B, a cysteine proteinase, was studied. Formalin-fixed paraffin-embedded specimens from 13 patients who had squamous cell carcinomas (SCC) with local recurrence, skin and/or lymph node metastasis were examined. Cathepsin D stained intensely as a granular pattern (mature enzyme) in tumour cells of 69% of primary lesions and all the secondary lesions of the patients with SCC. Cathepsin B stained more intensely in SCC cells of all of the primary and secondary lesions than in normal epidermis; staining patterns were almost diffuse (procathepsin B). Granular and diffuse patterns (mature enzyme of cathepsin D and procathepsin B, respectively) appeared in the outer and inner parts of tumour islands, respectively. The presence of the active mature form of cathepsin D and procathepsin B in metastatic skin lesions of SCC was confirmed by Western blotting analysis. The presence and localization of the active mature form of cathepsin D suggests that activated cathepsin D may be involved in the invasion and metastasis of SCC.
...
PMID:Expression of cathepsin D and B in invasion and metastasis of squamous cell carcinoma. 934 30

Some proteolytic enzymes, trypsin, cathepsin B, cathepsin D, collagenase, elastase and their inhibitors, API and AMG, in serum of patients with colorectal carcinoma have been evaluated. Twenty patients belonged to stage B of colorectal carcinoma, twenty two patients to stage D (Astler and Coller classification) and a control group of thirty healthy volunteers were evaluated. Except in cathepsin D, patients exhibit higher enzymatic activities than healthy subjects, and both groups have all the proteolytic activities assayed in serum. Patients with disseminated disease have increased cathepsin B and collagenase levels, with a decrease of trypsin activity, showing an increment in API and AMG in sera. However, only the API values were significantly higher in patients with metastases. The coexistence of proteolytic activities in human sera together with their inhibitors is considered as well as the origin of these, tumoral and/or reactive, increments. Cathepsin B levels are raised in colorectal neoplasms and contribute to the destruction of the extracellular matrix and the proliferation of tumoral cells. There is evidence that a relation between collagenase like activity and tumor invasiveness exists. Cathepsin B and collagenase increases agree with the tumoral mass. On the other hand, trypsin decrease in metastatic carcinoma is probably related to the increment of their inhibitors, API and AMG, acute phase reactant proteins.
...
PMID:Serum proteolytic activities and antiproteases in human colorectal carcinoma. 973 3

Analyses using either one or two-dimensional gel electrophoresis were performed to identify the contribution of several proteases to lower molecular weight (MW) neurofilament 68 (NF68) break down products (BDPs) detected in cortical homogenates following unilateral cortical impact injury in rats. One dimensional immunoblot of BDPs obtained from in vitro cleavage of enriched neurofilaments (NF) by purified micro-calpain, m-calpain, cathepsin, B, cathepsin D, and CPP32 (caspase-3) were compared to in vivo samples from rats following traumatic brain injury (TBI). Comparison of these blots provided information on the relative contribution of different cysteine or aspartic proteases to NF loss following brain injury. As early as 3 hrs post-injury, cortical impact resulted in the presence of several lower MW NF68 immunopositive bands having patterns similar to those previously reported to be produced by calpain mediated proteolysis of neurofilaments. Only micro-calpain and m-calpain in vitro digestion of enriched neurofilaments contributed to the presence of the low MW 57 kD NF68 break down product (BDP) detected in post-TBI samples. Cathepsin B, cathepsin D, and caspase-3 failed to produce either the 53 kD or 57 kD NF BDPs. Further, 1 and 2 dimensional peptide maps containing a 1:1 ratio of in vivo and in vitro tissue samples showed complete comigration of lower MW immunopositive spots produced by TBI or in vitro incubation with m-calpain, thus providing additional evidence for the potential role of calpain activation to the production of NF68 BDPs following TBI. More importantly, 2-dimensional gel electrophoresis detected that immunopositive NF68 spots shifted to the basic pole (+) suggesting that dephosphorylation of the NF68 subunit pool may be associated with NF protein loss following TBI, an observation not previously noted in any model of experimental brain injury.
...
PMID:Immunoblot analyses of the relative contributions of cysteine and aspartic proteases to neurofilament breakdown products following experimental brain injury in rats. 980 82

Cathepsin B (CB) is a thiol-stimulated protease implicated in cancer invasion and metastasis. Other proteases involved in cancer spread such as urokinase-type plasminogen activator (uPA) and cathepsin D have previously been shown to be prognostic markers in breast cancer. CB was assayed by ELISA in 193 patients with primary breast cancer. CB levels were significantly higher in both primary and metastatic breast tumors than in fibroadenomas (p = 0.0001). In the primary carcinomas, CB levels showed no significant correlation with either nodal status, tumor size or estrogen receptor (ER) status. Patients with primary breast cancers containing high levels of CB had a significantly shorter disease-free interval (p = 0.01, chi-square = 6.61) and overall survival (p = 0.014, chi-square = 6.08) than patients with low levels of the protease. However, in multivariate analysis, using nodal status, tumor size, ER status and urokinase plasminogen activator (uPA), CB was not an independent prognostic marker. In contrast, nodal status, ER status and uPA were prognostic in multivariate analysis. In conclusion, CB, like certain other proteases implicated in cancer metastasis, correlates with poor outcome in patients with breast cancer. These results thus support the evidence from model systems linking CB to cancer spread. Inhibition of CB expression or activity might therefore be exploited for anti-metastatic therapies.
...
PMID:High levels of cathepsin B predict poor outcome in patients with breast cancer. 1007 87

PC12 cells undergo apoptosis when cultured under conditions of serum deprivation. In this situation, the activity of caspase-3-like proteinases was elevated, and the survival rate could be maintained by treatment with acetyl-DEVD-cho, a specific inhibitor of caspase-3. In a culture of PC12 cells treated with acetyl-DEVD-cho, where caspase-3-like proteinases are not activated, CA074, a specific inhibitor of cathepsin B induced active death of the cells. Cathepsin B antisense oligonucleotides showed a similar effect to CA074 on the induction of active cell death. By double staining of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling and activated caspase-3, the dying cells treated with CA074 were positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining but negative for activated caspase-3. Ultrastructurally, the cells were relatively large and had nuclei with chromatin condensation. The initiation of cell death by CA074 or the cathepsin B antisense were inhibited by the addition of pepstatin A, a lysosomal aspartic proteinase inhibitor, or by cathepsin D antisense. To examine whether this cell death pathway was present in cell types other than PC12 cells, we analysed dorsal root ganglion neurons obtained from rat embryos on the 15th gestational day, a time when they require nerve growth factor for survival and differentiation in culture. When cultured in the absence of nerve growth factor, the neurons survived in the presence of acetyl-DEVD-cho or acetyl-YVAD-cho. Under these conditions, CA074 reduced the survival rate of the neurons, which was subsequently restored by the further addition of pepstain A. These results suggest that a novel pathway for initiating cell death exists which is regulated by lysosomal cathepsins, and in which cathepsin D acts as a death factor. We speculate that this death-inducing activity is normally suppressed by cathepsin B.
...
PMID:Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases. 1033 74

Osteoclasts are macrophage-derived polykaryons that degrade bone in an acidic extracellular space. This differentiation includes expression of proteinases and acid transport proteins, cell fusion, and bone attachment, but the sequence of events is unclear. We studied two proteins expressed at high levels only in the osteoclast, cathepsin K, a thiol proteinase, and tartrate-resistant acid phosphatase (TRAP), and compared this expression with acid transport and bone degradation. Osteoclastic differentiation was studied using human apheresis macrophages cocultured with MG63 osteosarcoma cells, which produce cytokines including RANKL and CSF-1 that mediate efficient osteoclast formation. Immunoreactive cathepsin K appeared at 3-5 days. Cathepsin K activity was seen on bone substrate but not within cells, and cathepsin K increased severalfold during further differentiation and multinucleation from 7 to 14 days. TRAP also appeared at 3-5 d, independently of cell fusion or bone attachment, and TRAP activity reached much higher levels in osteoclasts attached to bone fragments. Two proteinases that occur in the precursor macrophages, cathepsin B, a thiol proteinase related to cathepsin K, and an unrelated lysosomal aspartate proteinase, cathepsin D, were also studied to determine the specificity of the differentiation events. Cathepsin B occurred at all times, but increased two- to threefold in parallel with cathepsin K. Cathepsin D activity did not change with differentiation, and secreted activity was not significant. In situ acid transport measurements showed increased acid accumulation after 7 days either in cells on osteosarcoma matrix or attached to bone, but bone pit activity and maximal acid uptake required 10-14 days. We conclude that TRAP and thiol proteinase expression begin at essentially the same time, and precede cell fusion and bone attachment. However, major increases in acid secretion and proteinases expression continue during cell fusion and bone attachment from 7 to 14 days.
...
PMID:Proteinase expression during differentiation of human osteoclasts in vitro. 1086 60

Cathepsin B, a lysosomal cysteine protease, is synthesized as a glycoprotein with two N-linked oligosaccharide chains, one of which is in the propeptide region while the other is in the mature region. When cultured rat hepatocytes were labeled with [(32)P]phosphate, (32)P-labeled cathepsin B was immunoprecipitated only in the proform from cell lysates and medium. Either Endo H or alkaline phosphatase treatment of (32)P-labeled procathepsin B demonstrated the acquisition of a mannose 6-phosphate (Man 6-P) residue on high mannose type oligosaccharides. To identify the site of phosphorylation, immunoisolated (35)S- or (32)P-labeled procathepsin B was incubated with purified lysosomal cathepsin D, since cathepsin D cleaves 48 amino acid residues from the N-terminus of procathepsin B, in which one N-linked oligosaccharide chain was also included [Kawabata, T. et al. (1993) J. Biochem. 113, 389-394]. Treatment of intracellular (35)S-labeled procathepsin B with a molecular mass of 39-kDa with cathepsin D resulted in the production of the 31-kDa intermediate form, but the (32)P-label incorporated into procathepsin B disappeared after treatment with cathepsin D. These results indicate that the phosphorylation of procathepsin B is restricted to an oligosaccharide chain present in the propeptide region. Interestingly, cathepsin B sorting to lysosomes was not inhibited by NH(4)Cl treatment and about 90% of the intracellular procathepsin B initially phosphorylated was secreted into the medium without being dephosphorylated intracellularly, and did not bind significantly to cation-independent-Man 6-P receptor, suggesting the failure of Man 6-P-dependent transport of procathepsin B to lysosomes. Additionally, about 50% of the newly synthesized (35)S-labeled cathepsin B was retained in the cells in mature forms consisting of a 29-kDa single chain form and a 24-kDa two chain form, while part of the procathepsin B was associated with membranes in a Man 6-P-independent manner. Taken together, these results show that in rat hepatocytes, cathepsin B is targeted to lysosomes by an alternative mechanism(s) other than the Man 6-P-dependent pathway.
...
PMID:Lysosomal cysteine protease, cathepsin B, is targeted to lysosomes by the mannose 6-phosphate-independent pathway in rat hepatocytes: site-specific phosphorylation in oligosaccharides of the proregion. 1087 56


<< Previous 1 2 3 4 5 Next >>

---