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

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antisperm antibodies (ASA) are the main cause of immunological infertility, as they impair sperm function by binding to the sperm membrane. In this study, we isolated highly enriched sperm membrane proteins by two-dimensional (2D) gel electrophoresis. Isoelectric focusing, as a first dimension, was performed on precast DryStrip IPG 4-7. The second dimension was carried out on 12% sodium dodecyl sulphate-polyacrylamide gels. A total of 18 antigens were identified by the subsequent 2D Western blotting using ASA from seminal plasma samples of infertile patients. Six of the recognized proteins were isolated and analysed by means of mass spectrometry and peptide matching. They were identified as heat shock proteins HSP70 and HSP70-2, the disulphide isomerase ER60, the inactive form of caspase-3 and two subunits of the proteasome (component 2 and zeta chain). The biochemical identification of these proteins will be helpful in understanding the mechanisms by which ASA impair both sperm function and fertilization. Thus, these proteins may also be useful in the development of reliable methods for ASA detection.
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PMID:Isolation and identification of sperm membrane antigens recognized by antisperm antibodies, and their possible role in immunological infertility disease. 1116 Aug 36

Membrane cofactor protein (MCP; CD46) is a complement regulator widely expressed as four isoforms that arise via alternative splicing. On human spermatozoa, MCP is expressed on the inner acrosomal membrane and alterations of spermatozoa MCP may be associated with infertility. In rodents, expression of MCP is largely restricted to the testes. MCP on human spermatozoa has a unique M(r) pattern that we have investigated. We also characterized MCP expression in mice transgenic (tg) for human MCP. Human MCP expression in the tg mice mimics the human pattern in that it is located on the inner acrosomal membrane and has a faster M(r) than MCP expressed elsewhere. Sequencing of RT-PCR products from the testis indicates that there is not a unique male reproductive tissue specific cytoplasmic tail. Instead, human spermatozoa express MCP bearing cytoplasmic tail two, which is also utilized in most other tissues and contains several signaling motifs. Further, using N-glycosidases, we demonstrate that the unique lower molecular weight of MCP on spermatozoa is secondary to a modification in the N-linked sugars. Specifically, as the spermatozoa mature, but before they reach the epididymis, the three N-linked sugars of MCP are trimmed to less complex structures. While the purpose of this deglycosylation is unknown, we propose that it is a common feature of proteins expressed on the plasma and inner acrosomal membranes of spermatozoa and hypothesize that it is a spermatozoa specific event critical for facilitating sperm-egg interactions.
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PMID:Characterization of human membrane cofactor protein (MCP; CD46) on spermatozoa. 1211 88

Ubiquitin and ubiquitin-like proteins control the degradation of substrates as diverse as cyclins, viral envelope proteins, plasma membrane receptors, and mRNAs. The ubiquitinated substrates are targeted towards the lysosomal or proteasomal degradation sites. The number and position of ubiquitin molecules bound to substrates' lysine residues and the number and position of ubiquitin molecules in polyubiquitin chains determine the astonishing substrate specificity of ubiquitin-mediated proteolysis. Ubiquitin is likely to be expressed in mammalian gametes and embryos at any given developmental step, but the information on ubiquitin dependence of gametogenesis and fertilization is sketchy. Ubiquitin ligases E1, E2, E3, and UBC4 are active in the testis. Ubiquitin and proteasomal subunits can be detected in the human sperm centrosome that undergoes dramatic reduction during spermatid elongation. Spermatid histones are ubiquitinated as they are being transiently replaced by transitional proteins and permanently by protamines. Ubiquitin tagging of the sperm mitochondrial membranes may serve as a death sentence for paternal mitochondria at fertilization, thus promoting the maternal inheritance of mitochondrial DNA (mtDNA) in mammals. The defective spermatozoa become surface-ubiquitinated during sperm descent down the epididymis. Finally, new evidence suggests the involvement of ubiquitin-proteasome pathway in the zona penetration by the acrosome-reacted spermatozoon. Such differential patterns of ubiquitination in the testis and epididymis, and inside the egg, may be necessary for reproductive success in humans and animals. Deciphering and eventually manipulating the ubiquitin-dependent proteolysis in the reproductive system could allow us to redirect the mode of mtDNA inheritance after cloning and ooplasmic transplantation, provide germ line therapy in some cases of male infertility, develop new contraceptives, manage polyspermia during in vitro fertilization, and establish objective markers for infertility diagnostics, semen evaluation, and prediction of future fertility.
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PMID:Ubiquitin-dependent proteolysis in mammalian spermatogenesis, fertilization, and sperm quality control: killing three birds with one stone. 1267 25

The cell cycle is the process by which cells grow, replicate their genome and divide. The cell cycle control system is a cyclically-operating biochemical device constructed from a set of interacting proteins that induce and coordinate proper progression through the cycle, and includes cyclins, cyclin-dependent kinases (CDK) and their inhibitors (CDKI). There are mainly two families of CDKI, the INK family (INK4a/p16; INK4b/p15; INK4c/p18 and INK4d/p19) and the WAF/KIP family (WAF1/p21; KIP1/p27; KIP2/p57). Progression through the cell cycle is mainly dependent on fluctuations in the concentration of cyclins and CDKI achieved through the programmed degradation of these proteins by proteolysis within the ubiquitin-proteasome system. There is also a transcriptional regulation of cyclin expression, probably dependent on CDK phosphorylation. The p53 family--p53, p63 and p73--function as transcription factors that play a major role in regulating the response of mammalian cells to stressors and damage, in part through the transcriptional activation of genes involved in cell cycle control (e.g. p21), DNA repair, senescence, angiogenesis and apoptosis. Essential for the maintenance of euploidy during mitosis is human securin, identical to the product of the pituitary tumour-transforming gene (PTTG). Loss of regulation at the G1/S transition appears to be a common event among virtually all types of human tumours. Aberrations of one or more components of the pRb/p16/cyclin D1/CDK4 pathway seem to be a frequent event (80%) in pituitary tumours. The role of p27 is rather that of a haploinsufficient gene. p27-/- mice show an increased growth rate, due to increased cellularity, testicular and ovarian cell hyperplasia and infertility, and hyperplasia of the pituitary intermediate lobe with nearly 100% mortality caused by such a benign pituitary tumour. Although the p27 gene was not found to be mutated in human pituitary tumours and its mRNA expression was similar in tumour samples in comparison with normal pituitaries, the load of p27 protein expression in corticotroph adenomas and pituitary carcinomas was shown to be much lower than those in normal pituitary tissue or other types of pituitary adenoma, suggesting that post-translational processing of p27 accelerates its removal from the nucleus. In respect to p27 degradation and its cellular compartmentalization, several pathways have been explored. Malignant tumours are associated with increased nuclear immunostaining for Jun-activation binding protein-1 (Jab1) which is responsible for phosphorylated p27 export from the nucleus. Corticotrophinomas are characterized by massively increased phosphorylation of p27 on Thr187, but are not associated with changes in Jab1. Macrophage inhibitory factor (MIF), which binds and inactivates Jab1, was noted to be over-expressed in tumours with abundant Jab1, suggesting that it may be part of a compensatory mechanism to moderate Jab1 activity. Proteasomal degradation of p27 requires its ubiquitylation by the SCF ubiquitin ligase, with specific addressing by the F-box protein Skp2 and its co-factor Cks1. Pituitary tumours with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 immunostaining, suggesting that increased Skp2 could play at least a part in this process. No difference was observed in Cks1 mRNA levels between normal pituitaries and pituitary adenomas. The present data suggest that inhibition of growth and tumour development is sensitive not only to the absolute levels of p27 protein, but also to its cellular compartmentalization. Very recent findings from our group have established up-regulation of the serine-threonine kinase Akt in pituitary tumours compared to normal pituitary, which may cause phosphorylation of p27 on Thr157 and cytoplasmic retention of p27. PTTG protein is highly expressed in various human tumours, including pituitary tumours. While its mRNA levels are low in normal pituitary, increases in PTTG transcripts from more than 50% to more than 10-fold were recorded in the majority of a series of pituitary adenomas. Control of the cell cycle is a vital part of the cell's replication machinery. Disruption of this process is commonly seen in pituitary tumours and we are now beginning to identify regulatory elements which are likely to play a major role in pituitary oncogenesis.
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PMID:Cell cycle dysregulation in pituitary oncogenesis. 1528 39

Sulfasalazine (SASP) has been reported to depress the fertility in men and experimental male animals, but the fundamental mechanisms of infertility caused by SASP are still unknown. This study was designed to investigate the mechanisms of infertility in rats treated with SASP at a dose of 600 mg/kg for 28 days, including monitoring of sperm motility using computer associated sperm analysis system and acrosome reaction by FITC-concanavalin A lectin staining. The sperm motility and acrosome reaction, which are important for fertilization, were significantly reduced by SASP. Furthermore, to investigate the molecular mechanisms of infertility induced by SASP, mRNA expression analysis in the testes was performed using cDNA microarray as a first screening. It was revealed that CD59, which is located on the acrosomal membrane and is known to be important for the reproductive function of sperm, was affected in the testes; this was also confirmed by real-time PCR analysis, but the spermatogenesis-related genes examined in this study were not affected. Therefore, we focused on CD59 and two other acrosome membrane related-genes: MCP and DAF. CD59, MCP, and DAF in the epididymides of SASP-treated rats were significantly decreased as assessed by real-time RT-PCR analysis and additionally, the expression of CD59 protein was found to be decreased by Western blotting. These results allowed us to hypothesize that the suppression of epididymal acrosomal membrane proteins synthesis with their consequent reduced incorporation to the sperm membrane leads to a depressed sperm motility and acrosome reaction, and thereby leads to infertility in SASP treated male rats.
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PMID:Effects of sulfasalazine on sperm acrosome reaction and gene expression in the male reproductive organs of rats. 1562 86

Genetic and biochemical analyses have uncovered an essential role for nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating phase II xenobiotic metabolism and antioxidant response. Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice. Nrf2-/- female mice exposed to VCD exhibit an age-dependent decline in reproduction leading to secondary infertility accompanied by hypergonadotropic hypogonadism after 30 weeks of age. VCD is shown to selectively destroy small ovarian follicles, resulting in early depletion of functional follicles. Treatment with VCD induces apoptotic death in cultured cells and in ovarian follicles, suggesting apoptosis as a mechanism of follicle loss. Loss of Nrf2 function blocks the basal and inducible expression of microsomal epoxide hydrolase, a key enzyme in the detoxification of VCD, and increases the oxidative stress in cells that is further exacerbated by VCD. Foxo3a, a repressor in the early stages of follicle activation, displays reduced expression in Nrf2-/- ovaries, causing accelerated growth of follicles in the absence of exposure to exogenous chemicals. Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization. This study demonstrates that Nrf2 serves as an essential sensor and regulator of chemical homeostasis in ovarian cells, protecting the cells from toxic chemicals by controlling metabolic detoxification, reactive oxygen species defense, and Foxo3a expression. In addition, these findings raise the possibility that exposure to environmental or occupational ovotoxicants plays a role in the premature ovarian failure commonly associated with infertility and premature aging in women.
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PMID:Accelerated ovarian failure induced by 4-vinyl cyclohexene diepoxide in Nrf2 null mice. 1642 48

Theophylline (THP) and 1,3-dinitrobenzene (DNB) are thought to induce infertility by incapacitating the nurturing Sertoli cells and causing germ cell apoptosis in the testicular seminiferous epithelium, respectively. We hypothesized that THP and DNB exposure would alter the expression of the genes within the ubiquitin-proteasome pathway (UPP), implicated in spermatogenesis and epididymal sperm quality control. Rats were fed 0 or 8000 ppm of THP and necropsied on Days 18, 30, and 42 or administered 0, 2, or 6 mg/kg DNB via oral gavage and necropsied on Day 7. Tissues were collected from the testis and the caput, corpus, and cauda regions of the epididymis for transcriptional profiling by semiquantitative RT-PCR, real-time RT-PCR, and histopathology. Target UPP genes included those encoding for constitutive the 20S proteasomal core subunits Psmb1 (beta1), Psmb2 (beta2), and Psmb5 (beta5); the inducible 20S core subunits Psmb9 (LMP2), Psmb8 (LMP7), and Psmb10 (LMP10); and Ube1 (ubiquitin-activating enzyme E1), Ube2d3 (ubiquitin-conjugating enzyme E2), and Uchl1 (ubiquitin C-terminal hydrolase PGP9.5). Spermatozoa were collected from the cauda epididymis for analysis by light microscopy and flow cytometric evaluation of sperm surface ubiquitin. These data show that reprotoxic exposure alters the tissue-specific expression of UPP genes in the testis and epididymis, which may contribute to the aberrant spermatogenesis and epididymal processing of both normal and defective spermatozoa. Transcriptional profiling and flow cytometric analysis of the UPP thus captures the prodromal effects of reproductive toxicity not captured by conventional histology and functional cytology. Complementing seminal analysis with these measures may be useful in screening drug-induced toxicity or environmental infertility.
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PMID:Differential expression of genes encoding constitutive and inducible 20S proteasomal core subunits in the testis and epididymis of theophylline- or 1,3-dinitrobenzene-exposed rats. 1698 15

Despite years of research work, biologists remain divided over the issue of zona pellucida function during fertilization and the mode of sperm-ZP penetration. The present review examines the emerging evidence for the participation of ubiquitin-proteasome pathway in the process of sperm-ZP penetration generated in the last five years in species of mammals, ascidians and invertebrates. The 26S proteasome, a multi-subunit protease, selectively recognizes, and degrades, egg coat substrate proteins tagged by a covalent ligation of a small, multimeric protein, ubiquitin. Our in vitro work with pig gametes indicates that the sperm-borne 26S proteasomes selectively degrade an ubiquitinated ZP (glyco)protein during fertilization. We suggest that one or more of the ZP proteins are ubiquitinated, and proteasomes associated with the inner acrosomal membrane, are exposed as a result of acrosomal exocytosis. Sperm-ZP penetration may involve the ZP-deubiquitination, with several proteasomal subunits becoming phosphorylated. Polyubiquitin chain recognition activities associated with the sperm acrosomal proteasome could also contribute to anti-polyspermy control after sperm-egg fusion. Here, we bring together the relevant recent data on the mechanism of sperm-ZP penetration in mammals. Such observations could possibly lead to the development of novel non-hormonal contraceptives, improvement of infertility diagnostics and optimization of assisted reproduction.
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PMID:Mechanism of sperm-zona pellucida penetration during mammalian fertilization: 26S proteasome as a candidate egg coat lysin. 1756 86

Ubiquitin is encoded in mice by two polyubiquitin genes, Ubb and Ubc, that are considered to be stress inducible and two constitutively expressed monoubiquitin (Uba) genes. Here we report that targeted disruption of Ubb results in male and female infertility due to failure of germ cells to progress through meiosis I and hypogonadism. In the absence of Ubb, spermatocytes and oocytes arrest during meiotic prophase, before metaphase of the first meiotic division. Although cellular ubiquitin levels are believed to be maintained by a combination of functional redundancy among the four ubiquitin genes, stress inducibility of the two polyubiquitin genes, and ubiquitin recycling by proteasome-associated isopeptidases, our results indicate that ubiquitin is required for and consumed during meiotic progression. The striking similarity of the meiotic phenotype in Ubb(-/-) germ cells to the sporulation defect in fission yeast (Schizosaccharomyces pombe) lacking a polyubiquitin gene suggests that a meiotic role of the polyubiquitin gene has been conserved throughout eukaryotic evolution.
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PMID:The mouse polyubiquitin gene Ubb is essential for meiotic progression. 1807 Sep 17

The procera (pro) mutant of tomato exhibits a well-characterized constitutive gibberellic acid (GA) response phenotype. The tomato DELLA gene LeGAI in the pro mutant background contains a point mutation that results in an amino acid change in the conserved VHVID putative DNA-binding domain in LeGAI to VHEID. This same point mutation is in four different genetic backgrounds exhibiting the pro phenotype, suggesting that this mutation co-segregates with the pro phenotype. Complementation of the mutant with a constitutively expressed wild-type LeGAI gene sequence was not conclusive due to the infertility of transgenic plants. The pro mutation alters tomato branching architecture through differential suppression of axillary bud development, indicating a role for DELLA proteins in the regulation of plant structure. Isolated gib-1 pro double mutant embryo axes, which are unable to synthesize GA, germinate faster than their wild-type counterparts, and exert greater embryo growth potential. The pro mutation is therefore regulating GA responses within the tomato embryo. Transient expression of a LeGAI-GFP (green fluorescent protein) fusion protein in onion epidermis results in its location to the nucleus, and this protein is rapidly degraded by the proteasome in the presence of GA.
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PMID:Procera is a putative DELLA mutant in tomato (Solanum lycopersicum): effects on the seed and vegetative plant. 1825 77


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