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cathepsin B OKDB#: 1099
 Symbols: CTSB Species: human
 Synonyms: APPS, CPSB  Locus: 8p23.1 in Homo sapiens


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General Comment Cathepsins H (CTSH), L (CTSL), B (CTSB) and S (CTSS) are papain family cysteine proteinases involved in a variety of physiologic processes such as proenzyme activation, enzyme inactivation, antigen presentation, hormone maturation, tissue remodeling, and bone matrix resorption.

NCBI Summary: This gene encodes a member of the C1 family of peptidases. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the cathepsin B light and heavy chains, which can dimerize to form the double chain form of the enzyme. This enzyme is a lysosomal cysteine protease with both endopeptidase and exopeptidase activity that may play a role in protein turnover. It is also known as amyloid precursor protein secretase and is involved in the proteolytic processing of amyloid precursor protein (APP). Incomplete proteolytic processing of APP has been suggested to be a causative factor in Alzheimer's disease, the most common cause of dementia. Overexpression of the encoded protein has been associated with esophageal adenocarcinoma and other tumors. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Nov 2015]
General function Cell death/survival, Apoptosis, Enzyme, Hydrolase, Peptidase/Protease
Comment
Cellular localization Secreted, Cytoplasmic
Comment
Ovarian function Early embryo development
Comment Inhibition of cathepsin B activity prevents deterioration in the quality of in vitro aged porcine oocytes. Liang S et al. (2018) The activity of cathepsin B, a member of the lysosomal protease family, directly correlates with oocyte quality and subsequent embryonic development. However, its biological function during the progression of in vitro aging of oocytes in pigs has not been demonstrated. Here, we showed that cathepsin B activity was dramatically increased during in vitro aged oocytes. The inhibition of cathepsin B activity prevented the decline of the quality of aged oocytes and improved their subsequent developmental competence. Moreover, the inhibition of cathepsin B activity reduced aging-induced mitochondrial dysfunction and attenuated oxidative stress. The inhibition of cathepsin B activity also markedly decreased early apoptosis levels and the frequency of spindle anomalies during in vitro aging of oocytes. These results demonstrate that in vitro aging of oocytes induces cathepsin B activity, which is associated with a decline in oocyte quality. The inhibition of cathepsin B activity has a beneficial effect on oocytes during the process of in vitro aging.////////////////// Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity. Templeman NM et al. (2018) A decline in female reproduction is one of the earliest hallmarks of aging in many animals, including invertebrates and mammals 1-4]. The insulin/insulin-like growth factor-1 signaling (IIS) pathway has a conserved role in regulating longevity [5] and also controls reproductive aging [2, 6]. Although IIS transcriptional targets that regulate somatic aging have been characterized [7, 8], it was not known whether the same mechanisms influence reproductive aging. We previously showed that Caenorhabditis elegans daf-2 IIS receptor mutants extend reproductive span by maintaining oocyte quality with age [6], but IIS targets in oocytes had not been identified. Here, we compared the transcriptomes of aged daf-2(-) and wild-type oocytes, and distinguished IIS targets in oocytes from soma-specific targets. Remarkably, IIS appears to regulate reproductive and somatic aging through largely distinct mechanisms, although the binding motif for longevity factor PQM-1 [8] was also overrepresented in oocyte targets. Reduction of oocyte-specific IIS targets decreased reproductive span extension and oocyte viability of daf-2(-) worms, and pqm-1 is required for daf-2(-)'s long reproductive span. Cathepsin-B-like gene expression and activity levels were reduced in aged daf-2(-) oocytes, and RNAi against cathepsin-B-like W07B8.4 improved oocyte quality maintenance and extended reproductive span. Importantly, adult-only pharmacological inhibition of cathepsin B proteases reduced age-dependent deterioration in oocyte quality, even when treatment was initiated in mid-reproduction. This suggests that it is possible to pharmacologically slow age-related reproductive decline through mid-life intervention. Oocyte-specific IIS target genes thereby revealed potential therapeutic targets for maintaining reproductive health with age.////////////////// Identification of Novel Bovine Cumulus Cell Molecular Markers Predictive of Oocyte Competence: Functional and Diagnostic Implications. [Bettegowda A et al. The present study was undertaken to discover molecular markers in bovine cumulus cells predictive of oocyte competence and elucidate their functional significance. Differences in RNA transcript abundance in cumulus cells harvested from oocytes of adult versus prepubertal animals (model of poor oocyte quality) were identified by microarray analysis. Four genes of interest encoding for the lysosomal cysteine proteinases cathepsin B, S, K and Z and displaying greater transcript abundance in cumulus cells surrounding oocytes harvested from prepubertal animals were chosen for further investigation. Greater mRNA abundance for such genes in cumulus cells of prepubertal oocytes was confirmed by real time RT-PCR. Elevated transcript abundance for cathepsins B, S and Z was also observed in cumulus cells surrounding adult metaphase II oocytes that developed to the blastocyst stage at a low percentage following parthenogenetic activation, versus those that developed at a high percentage. Functional significance of cumulus cell cathepsin expression to oocyte competence was confirmed by treatment of cumulus oocyte complexes during in vitro oocyte maturation with a cell permeable cysteine proteinase (cathepsin) inhibitor. Inhibitor treatment decreased apoptotic nuclei in the cumulus layer and enhanced development of parthenogenetically activated and in vitro fertilized adult oocytes to the blastocyst stage. Stimulatory effects of inhibitor treatment during meiotic maturation on subsequent embryonic development were not observed when oocytes were matured in the absence of cumulus cells. Results support a functional role for cumulus cell cathepsins in compromised oocyte competence and suggest that cumulus cell cathepsin mRNA abundance may be predictive of oocyte quality.
Expression regulated by LH
Comment
Ovarian localization Oocyte, Granulosa, Surface epithelium
Comment Jokimaa et al reported the differential expression patterns of cathepsins B, H, K, L and S in the mouse ovary. Cathepsins B, H, K, L and S belong to a family of lysosomal cysteine proteinases which participate in a variety of proteolytic processes, including degradation of extracellular matrix. Although the presence of cathepsin mRNAs in the ovary has been reported earlier, very little information is available on their temporospatial expression. In the present study, Northern analysis revealed cyclic changes in the mRNA levels for cathepsins B, H, K, L and S during the 4-day oestrous cycle in the mouse ovary. Immunohistochemical localization revealed distinct expression patterns suggesting different functions for the cathepsins studied. Cathepsin B was predominantly seen in the germinal epithelium throughout the oestrous cycle. Upon follicular maturation, an increasing number of granulosa cells became positive for all cathepsins. Strong cathepsin H staining was sharply defined in theca externa which also stained for cathepsins K and S. Corpus luteum was the predominant location of cathepsin L. The distribution of cathepsin S resembled that of cathepsin L. The developing oocyte stained positive for all cathepsins. In-situ hybridization confirmed the differential production of cathepsin mRNAs by granulosa, thecal and luteal cells. These complex temporal and spatial expression patterns at different stages of the oestrous cycle and follicular development suggest divergent functions for specific cathepsins in follicular development, growth and rupture. Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Follicle stages Primary, Secondary, Antral, Preovulatory
Comment Liu HC, et al 2001 reported tha application of complementary DNA microarray (DNA chip) technology in the study of gene expression profiles during folliculogenesis. They used oligonucleotide microarray (DNA chip)-based hybridization analysis to gain a comprehensive view of gene expression and regulation involved in folliculogenesis. Preantral follicles isolated from day 14 B6D2F-1 mice were stimulated in vitro to form Graafian follicles. Total RNA extracted from the mouse preantral and Graafian follicles were reverse transcribed, labeled with digoxigenin-11-dUTP, and then hybridized with Clontech Atlas mouse cDNA expression arrays for comparison. Of 588 known studied genes, 39 and 61 were detected in preantral follicles and in Graafian follicles, respectively, and 17 were highly expressed consistently in both preantral and Graafian follicles. Performing clustering analysis, 46 were upregulated as the follicles advanced to mature stages. The CATHEPSIN B gene is up-regulated in the Graafian follicles.
Phenotypes
Mutations 1 mutations

Species: ovine
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Genome-wide differential expression profiling of mRNAs and lncRNAs associated with prolificacy in Hu sheep. Feng X et al. (2018) Reproductive ability, especially prolificacy, impacts sheep profitability. Hu sheep, a unique Chinese breed, is recognized for its high prolificacy, early sexual maturity, and year-round estrus. However, little is known about the molecular mechanisms underlying high prolificacy in Hu sheep. To explore the potential mRNAs and long non-coding RNAs (lncRNAs) involved in Hu sheep prolificacy, we performed an ovarian genome-wide analysis of mRNAs and lncRNAs(Kung, 2013 #2) during the follicular stage using Hu sheep of high prolificacy (HP, litter size = 3; three consecutive lambings) and low prolificacy (LP, litter size = 1; three consecutive lambings). Plasma LH concentration was higher in the HP group than in the LP group (P < 0.05) during the follicular stage. Subsequently, 76 differentially expressed mRNAs (DE-mRNAs) and five differentially expressed lncRNAs (DE-lncRNAs) were identified by pairwise comparison; qRT-PCR analysis of 10 randomly selected DE genes (mRNA and lncRNA) were consistent with the sequencing results. Gene Ontology analysis of DE-mRNAs revealed significant enrichment in immune response components, actin filament severingand phagocytosis. Pathway enrichment analysis of DE-mRNAs indicated a predominance of immune function pathways, including phagosomes, lysosomes and antigen processing. We constructed a co-expression network of DE-mRNAs and mRNA-lncRNAs, withC1qA,CD53,CTSB,CTSS,TYROBP, andAIF1as the hub genes. Finally, the expression of lysosomal protease cathepsin genes,CTSBandCTSD,were significantly upregulated in sheep ovaries in the HP group compared to the LP group (P < 0.05). These differential mRNAs and lncRNAs may provide information on the molecular mechanisms underlying sheep prolificacy.//////////////////

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created: Feb. 2, 2001, 4:27 p.m. by: hsueh   email:
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last update: May 29, 2018, 3:06 p.m. by: hsueh    email:



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