Ubiquitin carboxyl-terminal hydrolase L1 contributes to the oocyte selective elimination in prepubertal mouse ovaries

Shanghai Medical College of Fudan University, Shanghai, China.
Sheng li xue bao: [Acta physiologica Sinica] 05/2009; 61(2):175-84.
Source: PubMed


Apoptosis of abnormal oocytes is essential for defective oocyte elimination during prepubertal ovary development, and the ubiquitin system regulates the cell apoptosis via the degradation of specific proteins. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a component of the ubiquitin system, and the UCH-L1-dependent apoptosis is important for spermatogenesis. In the present study, the change in the number of follicles and the expression of UCH-L1 in oocytes were determined in prepubertal mouse ovaries by immunohistochemical techniques. A significant decrease in the follicular pool was found in prepubertal mouse ovaries during the period of day 21 to day 28 after birth, and accordingly, the UCH-L1 protein expression was increased, to some degree in association with Jun activation domain-binding protein 1 (Jab1) and cyclin-dependent kinase inhibitor p27(Kipl). The increased UCH-L1 protein, together with the corresponding changes of Jab1 was detected in morphologically abnormal oocytes of prepubertal ovaries. Through the immunofluorescent colocalization, UCH-L1 was shown concentrating in abnormal oocytes, and a parallel change in Jab1 was also seen. The affinity analysis confirmed the interaction between UCH-L1 and Jab1 in ovaries. These results suggest that UCH-L1 plays an important role, possibly in association with Jab1 and p27(Kipl), in selective elimination of abnormal oocytes during mouse prepubertal development.

Full-text preview

Available from:
  • Source
    • "UCH-L1 has been described as a tumor oncogene [23] [24] [25] and as a tumor suppressor gene influencing p53 and p27 Kip1 [26]. UCH-L1 interacts with p27 Kip1 through the generation of a heteromeric complex with the Jun activation domain-binding protein 1 (JAB-1) in ovaries [27] and lung cancer cells [28]. Nuclear translocation of both UCH-L1 and JAB-1 coincides with reduced nuclear levels of p27 Kip1 , proposing that UCH- L1 may contribute to p27 Kip1 degradation via its interaction and nuclear translocation with JAB-1 [28] in tumor cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Podocytes are terminally differentiated cells of the glomerular filtration barrier that react with hypertrophy in the course of injury such as in membranous nephropathy (MGN). The neuronal deubiquitinase ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed and activated in podocytes of human and rodent MGN. UCH-L1 regulates the mono-ubiquitin pool and induces accumulation of poly-ubiquitinated proteins in affected podocytes. Here, we investigated the role of UCH-L1 in podocyte hypertrophy and in the homeostasis of the hypertrophy associated "model protein" p27Kip1. A better understanding of the basic mechanisms leading to podocyte hypertrophy is crucial for the development of specific therapies in MGN. In human and rat MGN, hypertrophic podocytes exhibited a simultaneous up-regulation of UCH-L1 and of cytoplasmic p27Kip1 content. Functionally, inhibition of UCH-L1 activity and knockdown or inhibition of UCH-L1 attenuated podocyte hypertrophy by decreasing the total protein content in isolated glomeruli and in cultured podocytes. In contrast, UCH-L1 levels and activity increased podocyte hypertrophy and total protein content in culture, specifically of cytoplasmic p27Kip1. UCH-L1 enhanced cytoplasmic p27Kip1 levels by nuclear export and decreased poly-ubiquitination and proteasomal degradation of p27Kip1. In parallel, UCH-L1 increased podocyte turnover, migration and cytoskeletal rearrangement, which are associated with known oncogenic functions of cytoplasmic p27Kip1 in cancer. We propose that UCH-L1 induces podocyte hypertrophy in MGN by increasing the total protein content through altered degradation and accumulation of proteins such as p27Kip1 in the cytoplasm of podocytes. Modification of both UCH-L1 activity and levels could be a new therapeutic avenue to podocyte hypertrophy in MGN.
    Full-text · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
  • Source
    • "An involvement of the ubiquitin pathway in testis and spermatogenesis has been proposed for different organisms and testis-specific transcripts of different ubiquitin-interacting factors have been reported (for example [39-43]). Some data indicated an involvement of the ubiquitin pathway in the maintenance and development of ovarian germ cells in the fly [44] and the zebrafish [45] and during maturation of the ovary in mouse [46]. Several examples of maternally-expressed RING finger proteins with essential functions during development have been reported [47-51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Members of the makorin (mkrn) gene family encode RING/C3H zinc finger proteins with U3 ubiquitin ligase activity. Although these proteins have been described in a variety of eukaryotes such as plants, fungi, invertebrates and vertebrates including human, almost nothing is known about their structural and functional evolution. Via partial sequencing of a testis cDNA library from the poeciliid fish Xiphophorus maculatus, we have identified a new member of the makorin gene family, that we called mkrn4. In addition to the already described mkrn1 and mkrn2, mkrn4 is the third example of a makorin gene present in both tetrapods and ray-finned fish. However, this gene was not detected in mouse and rat, suggesting its loss in the lineage leading to rodent murids. Mkrn2 and mkrn4 are located in large ancient duplicated regions in tetrapod and fish genomes, suggesting the possible involvement of ancestral vertebrate-specific genome duplication in the formation of these genes. Intriguingly, many mkrn1 and mkrn2 intronless retrocopies have been detected in mammals but not in other vertebrates, most of them corresponding to pseudogenes. The nature and number of zinc fingers were found to be conserved in Mkrn1 and Mkrn2 but much more variable in Mkrn4, with lineage-specific differences. RT-qPCR analysis demonstrated a highly gonad-biased expression pattern for makorin genes in medaka and zebrafish (ray-finned fishes) and amphibians, but a strong relaxation of this specificity in birds and mammals. All three mkrn genes were maternally expressed before zygotic genome activation in both medaka and zebrafish early embryos. Our analysis demonstrates that the makorin gene family has evolved through large-scale duplication and subsequent lineage-specific retroposition-mediated duplications in vertebrates. From the three major vertebrate mkrn genes, mkrn4 shows the highest evolutionary dynamics, with lineage-specific loss of zinc fingers and even complete gene elimination from certain groups of vertebrates. Comparative expression analysis strongly suggests that the ancestral E3 ubiquitin ligase function of the single copy mkrn gene before duplication in vertebrates was gonad-specific, with maternal expression in early embryos.
    Full-text · Article · Dec 2010 · BMC Genomics
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the biological significance of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) involvement in oocyte maturation, we screened for proteins that bound to UCH-L1 in mouse ovaries, and we found that the prostate tumor overexpressed-1 (PTOV1) protein was able to bind to UCH-L1. PTOV1 is highly expressed in prostate cancers and considered as a potential marker for carcinogenesis and the progress of prostate cancer. It was reported that PTOV1 plays an important role in cell cycle regulation, but its role in mammalian oocyte development and meiosis is still unclear. In this paper, it was found that the expression levels of PTOV1 in mouse ovaries progressively increased from prepubescence to adulthood. And we found by immunohistochemistry that PTOV1 spreaded in both the cytoplasm and nuclei of oocytes during prepuberty, but in normal adult mouse oocytes, it concentrated not only in nuclei but also on the plasma membrane, though in some oocytes with abnormal shapes, PTOV1 did not display the typical distribution patterns. In granulosa cells, however, it was found to locate in the cytoplasm at all the selected ages. In postnatal mouse ovaries (28 days), estradiol treatment induced the adult-specific distribution pattern of PTOV1 in oocytes. In addition, UCH-L1 was shown to be associated with CDK1, which participated in the regulation of cell cycle and oocyte maturation. Therefore, we propose that the distribution changes of PTOV1 are age-dependent, and significant for mouse oocyte development and maturation. Moreover, the discovery that PTOV1 is associated with UCH-L1 in mouse oocytes supports the explanations for that UCH-L1 is involved in oocyte development and maturation, especially under the regulation of estrogen.
    No preview · Article · Jun 2011 · Histochemie
Show more