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)

Expression of proteolytic parameters of the urokinase-type plasminogen activator (uPA) system [uPA receptor (uPA-R), plasminogen activator inhibitor (PAI)-1] has been proven to be an independent prognostic parameter in cancer. However, it has not been considered that the uPA system is interacting with several other protease/inhibitor systems, neither has a comparable prognostic role of these factors been investigated. Moreover, studies evaluating specific protease patterns indicating high individual risk are missing completely. Therefore, in a consecutive prospective series of 203 gastric cancer patients, the expression of activators (plasminogen, tPA, MMP-2, cathepsin D, antithrombin 3) and inhibitors (alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, alpha-1-antichymotrypsin) of proteolysis was studied immunohistochemically in the tumor epithelium semiquantitatively (score 0-3) in addition to the uPA system. Kaplan-Meier analysis (median time of follow-up 31 months) revealed a significant association of cathepsin D (P=0.0042), alpha-2-macroglobulin (P=0.0281) and antitrypsin (P=0.0372) with disease-free survival and of cathepsin D (P=0.0018), antitrypsin (P=0.0112) and antichymotrypsin (P=0.0002) with overall survival. Multivariate Cox analysis performed to correct these results for relative impact of the uPA system and established prognostic factors showed PAI-1 (disease-free survival: P=0.002, relative risk 1.86; overall survival: P=0.005, relative risk 1.39), pT and pN as independent parameters. Cathepsin D was shown to have an independent impact on disease-free survival (P=0.020, relative risk 2.98). Comparative chi-square analysis of cases with poor and good prognoses revealed that in patients with good clinical outcome, inhibitors of proteolysis are correlated significantly, whereas in patients with poor prognosis activators of proteolysis are significantly associated preferentially and significant correlations with the uPA-R are dominant. For detailed pattern analysis, stepwise overall Kaplan-Meier analyses were performed in subgroups of high uPA-R-, uPA-, PAI1- and cathepsin D expression for two additional proteases each. From these analyses, the combination of high (score 2/3) expression of uPA-R, PAI-1, antichymotrypsin and alpha-2-macroglobulin was identified as a high-risk pattern, representing parameters known to be essential for uPA-R internalization and recycling. This suggests some of the uPA-associated proteases and inhibitors investigated as univariate prognostic parameters in gastric cancer. Cathepsin D is a new independent parameter for disease-free survival. The study further demonstrates that a protease pattern promoting uPA-R recycling in tumor cells especially indicates high individual risk tumors in gastric cancer.
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PMID:Tumor-associated proteases and inhibitors in gastric cancer: analysis of prognostic impact and individual risk protease patterns. 950 78

A mutant amyloid precursor protein (APP/RK) designed to interfere with processing by alpha-secretase caused a severe phenotype in transgenic mice, including behavioural abnormalities, i.e. neophobia, aggression, hypersensitivity to kainic acid, hyposensitivity to N-methyl-D-aspartate, and premature death [Moechars D. et al. (1996) Eur. molec. Biol. Org. J. 15, 1265-1274]. We now demonstrated that the APP/RK transgene did not disturb the expression of several other genes, i.e. endogenous amyloid precursor protein and amyloid precursor protein-like proteins, members of the low density lipoprotein receptor lipoprotein receptor family and several of their ligands, including apolipoprotein E, but expression of alpha-2-macroglobulin was never detected. Neither amyloid deposits nor neurofibrillary tangles were detected in the brain of APP/RK transgenic mice, even when 15-months-old. The tendency for seizures and hyposensitivity for N-methyl-D-aspartate was not due to or reflected in the distribution of the three major types of glutamate receptors. The major and consistent finding in transgenic APP/RK mice that died prematurely was extensive neurodegeneration and apoptosis, mainly in hippocampus and cortex, and accompanied by astrocytosis throughout the brain. Reduced synaptic density and dendritic damage was only observed in three transgenic mice that were killed shortly after positive observation of seizures. In addition, the distribution of cathepsin D and ubiquitin was abnormal in these mice.
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PMID:Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. 1039 65

There is considerable enthusiasm for the prospect of using common polymorphisms (primarily single nucleotide polymorphisms; SNPs) in candidate genes to unravel the genetics of complex disease. This approach has generated a number of findings of loci which are significantly associated with sporadic Alzheimer's disease (AD). In the present study, a total of 15 genes of interest were chosen from among the previously published reports of significant association in AD. Genotyping was performed on polymorphisms within those genes (14 SNPs and one deletion) using Dynamic Allele Specific Hybridization (DASH) in 204 Swedish patients with sporadic late-onset AD and 186 Swedish control subjects. The genes chosen for analysis were; low-density lipoprotein receptor-related protein (LRP1), angiotensin converting enzyme (DCP1), alpha-2-macroglobulin (A2M), bleomycin hydrolase (BLMH), dihydrolipoyl S-succinyltransferase (DLST), tumour necrosis factor receptor superfamily member 6 (TNFRSF6), nitric oxide synthase (NOS3), presenilin 1 (PSEN1), presenilin 2 (PSEN2), butyrylcholinesterase (BCHE), Fe65 (APBB1), oestrogen receptor alpha (ESR1), cathepsin D (CTSD), methylenetetrahydrofolate reductase (MTHFR), and interleukin 1A (IL1A). We found no strong evidence of association for any of these loci with AD in this population. While the possibility exists that the genes analysed are involved in AD (ie they have weak effects and/or are population specific), results reinforce the need for extensive replication studies if we are to be successful in defining true risk factors in complex diseases.
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PMID:Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease. 1143 25