Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein C inhibitor (PCI) is a nonspecific, heparin-binding serpin (serine protease inhibitor) that inactivates many plasmatic and extravascular serine proteases by forming stable 1:1 complexes. Proteases inhibited by PCI include the anticoagulant activated protein C, the plasminogen activator urokinase, and the sperm protease acrosin. In humans PCI circulates as a plasma protein but is also present at high concentrations in organs of the male reproductive tract. The biological role of PCI has not been defined so far. However, the colocalization of high concentrations of PCI together with several of its target proteases in the male reproductive tract suggests a role of PCI in reproduction. We generated mice lacking PCI by homologous recombination. Here we show that PCI(-/-) mice are apparently healthy but that males of this genotype are infertile. Infertility was apparently caused by abnormal spermatogenesis due to destruction of the Sertoli cell barrier, perhaps due to unopposed proteolytic activity. The resulting sperm are malformed and are morphologically similar to abnormal sperm seen in some cases of human male infertility. This animal model might therefore be useful for analyzing the molecular bases of these human conditions.
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PMID:Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility. 1112 Jul 60

Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. To investigate relative gene expression in human idiopathic non-obstructive azoospermia, we sequenced all the exons of cell division cycle 20 (CDC20) in 766 patients diagnosed with IA, as well as in 521 normally fertile men. Three novel missense mutations (S72G, R322Q, R383C) of CDC20 were detected and further confirmed by Sanger sequencing. The mRNA levels of securin, cyclin B, cyclin dependent kinase 1 (CDK1), and cyclin dependent kinase 2 (CDK2), which are all targeted for destruction via the anaphase-promoting complex/cyclosomeCDC20 (APC/CCDC20) pathway, were detected at relatively high levels using real-time quantitative polymerase chain reaction analysis. This demonstrated that the CDC20 R383C mutation led to dysfunction during the transition from metaphase to anaphase and facilitation of mitotic exit in vitro, and caused prolonged mitotic arrest during the cell cycle. This study suggests that a CDC20 R383C mutation may result in the pathogenesis of human IA.
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PMID:R383C mutation of human CDC20 results in idiopathic non-obstructive azoospermia. 2924 42

FZR1/CDH1 is an activator of Anaphase promoting complex/Cyclosome (APC/C), best known for its role as E3 ubiquitin ligase that drives the cell cycle. APC/C activity is regulated by CDK-mediated phosphorylation of FZR1 during mitotic cell cycle. Although the critical role of FZR1 phosphorylation has been shown mainly in yeast and in vitro cell culture studies, its biological significance in mammalian tissues in vivo remained elusive. Here, we examined the in vivo role of FZR1 phosphorylation using a mouse model, in which non-phosphorylatable substitutions were introduced in the putative CDK-phosphorylation sites of FZR1. Although ablation of FZR1 phosphorylation did not show substantial consequences in mouse somatic tissues, it led to severe testicular defects resulting in male infertility. In the absence of FZR1 phosphorylation, male juvenile germ cells entered meiosis normally but failed to enter meiosis II or form differentiated spermatids. In aged testis, male mutant germ cells were overall abolished, showing Sertoli cell-only phenotype. In contrast, female mutants showed apparently normal progression of meiosis. The present study demonstrated that phosphorylation of FZR1 is required for temporal regulation of APC/C activity at meiosis II entry, and for maintenance of spermatogonia, which raised an insight into the sexual dimorphism of FZR1-regulation in germ cells.
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PMID:Phosphorylation of the Anaphase Promoting Complex activator FZR1/CDH1 is required for Meiosis II entry in mouse male germ cell. 3257 94

The impact of smoking on male fertility has been extensively acknowledged. Many studies have shown that smoking reduces sperm production, motility and fertilizing capacity by increasing seminal oxidative stress and DNA damage. In this study, expression profiles of miRNAs and their predicted target genes, showing dysregulation in smokers and associated with male infertility, were obtained, using Gene Expression Omnibus (GEO) datasets. Differentially expressed miRNAs, related to male infertility in sperm samples of smoking and non-smoking men, were picked out using the GEO2R online tool. Then, the target genes of each selected miRNA were predicted by using MiR-DIP. The target genes lists were compared to differentially expressed genes from the smoking and infertile men datasets. Common genes were chosen for further enrichment analysis such as GO, KEGG and PPI network analysis via STRING and MCODE. Then, four miRNAs (miR-26a, miR-32, miR-188-3p and miR-512-3p) which had shown differential expression in male infertility in other studies, and also had differential expression in smoking men compared to non-smokers, were screened out. Moreover, a module consisting of eight genes was identified as hub genes, including APC, NIPBL, ARID4B, TNRC6A, GIGYF2, ELAVL1, RHOF and SRSF1. These were highly correlated with male infertility and impairment of spermatogenesis. This study provides a comprehensive bioinformatics analysis of miRNAs and their target genes affecting male infertility in smokers. The results showed a collection of the most relevant genes and effective molecular pathways, which may serve as potential markers for the early detection of spermatogenesis disorders leading to infertility in smokers, after experimental validation.
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PMID:Identification of miRNAs and the target genes related to male infertility and smoking using bioinformatics approaches. 3261 69