NCBI Summary:
The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]
A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes. Thomas C et al. (2021) Successful cell division relies on the timely removal of key cell cycle proteins such as securin. Securin inhibits separase, which cleaves the cohesin rings holding chromosomes together. Securin must be depleted before anaphase to ensure chromosome segregation occurs with anaphase. Here we find that in meiosis I, mouse oocytes contain an excess of securin over separase. We reveal a mechanism that promotes excess securin destruction in prometaphase I. Importantly, this mechanism relies on two phenylalanine residues within the separase-interacting segment (SIS) of securin that are only exposed when securin is not bound to separase. We suggest that these residues facilitate the removal of non-separase-bound securin ahead of metaphase, as inhibiting this period of destruction by mutating both residues causes the majority of oocytes to arrest in meiosis I. We further propose that cellular securin levels exceed the amount an oocyte is capable of removing in metaphase alone, such that the prometaphase destruction mechanism identified here is essential for correct meiotic progression in mouse oocytes.//////////////////Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II. Nabti I et al. (2017) Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase. In maternal ageing, oocytes show increased inter-sister kinetochore distance and premature sister chromatid separation (PSCS), suggesting aberrant separase activity. Here, we find that MII oocytes from aged mice have less securin than oocytes from young mice and that this reduction is mediated by increased destruction by the anaphase promoting complex/cyclosome (APC/C) during meiosis I (MI) exit. Inhibition of the spindle assembly checkpoint (SAC) kinase, Mps1, during MI exit in young oocytes replicates this phenotype. Further, over-expression of securin or Mps1 protects against the age-related increase in inter-sister kinetochore distance and PSCS. These findings show that maternal ageing compromises the oocyte SAC-APC/C axis leading to a decrease in securin that ultimately causes sister chromatid cohesion loss. Manipulating this axis and/or increasing securin may provide novel therapeutic approaches to alleviating the risk of oocyte aneuploidy in maternal ageing.//////////////////
Kakar SS et al cloned and sequenced the cDNA of a potent tumor transforming gene (TUTR1) from human testis and determined its
primary structure. Northern blot
analysis of the mRNA from various human tissues and tumors revealed that TUTR1 mRNA is highly expressed in tumors of
the pituitary gland, adrenal gland, ovary, endometrium, liver, uterus, and kidney as well as in cell lines derived from tumors
of the pituitary, breast, endometrium, and ovary. Overexpression of TUTR1 in mouse fibroblasts (NIH 3T3) cells resulted
in an increase in cell proliferation, induced cellular transformation in vitro, and promoted tumor formation in nude mice.
The influence of follicle size, FSH-enriched maturation medium, and early cleavage on bovine oocyte maternal mRNA levels. Mourot M et al. Transcription is arrested in the bovine oocyte within the first few hours of in vitro maturation, thus the stored maternal mRNAs accumulated in the oocyte are essential to sustain development until the Maternal-Zygotic Transition. In vivo matured oocytes have superior blastocyst formation rates than in vitro matured oocytes, suggesting that the mRNA content of these oocytes is of higher quality. To determine which transcripts may be associated with developmental competence, a Suppressive Subtractive Hybridization was performed between oocytes collected by ovariectomy at 6 hr post-LH surge and oocytes from slaughterhouse collected after 6 hr of maturation, resulting in a library enriched in these functionally important mRNAs. The clones were spotted onto a cDNA microarray and transcripts potentially associated with developmental competence were hybridized onto these slides. Hybridizations were performed with transcripts up-regulated in oocytes cultured for 6 hr in the presence or absence of rFSH in vitro, and secondly with transcripts up regulated in early-cleaving embryos versus those at the one-cell stage at 36 hr postfertilization. From these hybridizations, 13 candidates were selected. Their functional association with embryonic competence was validated by measuring their relative transcript levels by quantitative real-time PCR in eight different conditions: oocytes cultured with or without rFSH, early-versus late-cleaving embryos, and oocytes from different follicle sizes (1-3, 3-5, 5-8, and >8 mm of diameter). The gene candidates CCNB2, PTTG1, H2A, CKS1, PSMB2, SKIIP, CDC5L, RGS16, and PRDX1 showed a significant quantitative association with competence compared to BMP15, GDF9, CCNB1, and STK6. Mol. Reprod. Dev. (c) 2006 Wiley-Liss, Inc.
Cdc20 is critical for meiosis I and fertility of female mice. Jin F et al. Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C), initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1 Herbert M, et al .
Disjunction of pairs of homologous chromosomes during the first meiotic division (MI) requires anaphase-promoting complex (APC)-mediated activation of separase in budding yeast and Caenorhabditis elegans, but not Xenopus laevis. It is not clear which model best fits the mammalian system. Here we show that homologue disjunction in mouse oocytes is dependent on proteolysis of the separase inhibitor securin and the Cdk1 regulatory sub-unit cyclin B1. Proteolysis of both proteins was entirely dependent on their conserved destruction box (D-box) motifs, through which they are targeted to the APC. These data indicate that the mechanisms regulating homologue disjunction in mammalian oocytes are similar to those of budding yeast and C.elegans.
The human cumulus-oocyte complex gene-expression profile. Assou S et al. BACKGROUND: The understanding of the mechanisms regulating human oocyte maturation is still rudimentary. We have identified transcripts differentially expressed between immature and mature oocytes and cumulus cells. METHODS: Using oligonucleotide microarrays, genome-wide gene expression was studied in pooled immature and mature oocytes or cumulus cells from patients who underwent IVF. RESULTS: In addition to known genes, such as DAZL, BMP15 or GDF9, oocytes up-regulated 1514 genes. We show that PTTG3 and AURKC are respectively the securin and the Aurora kinase preferentially expressed during oocyte meiosis. Strikingly, oocytes overexpressed previously unreported growth factors such as TNFSF13/APRIL, FGF9, FGF14 and IL4 and transcription factors including OTX2, SOX15 and SOX30. Conversely, cumulus cells, in addition to known genes such as LHCGR or BMPR2, overexpressed cell-to-cell signalling genes including TNFSF11/RANKL, numerous complement components, semaphorins (SEMA3A, SEMA6A and SEMA6D) and CD genes such as CD200. We also identified 52 genes progressively increasing during oocyte maturation, including CDC25A and SOCS7. CONCLUSION: The identification of genes that were up- and down-regulated during oocyte maturation greatly improves our understanding of oocyte biology and will provide new markers that signal viable and competent oocytes. Furthermore, genes found expressed in cumulus cells are potential markers of granulosa cell tumours.
Follicle stages
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Wang Z et al. (2002) Tumorigenic pituitary tumor transforming gene (PTTG) is a mammalian homolog of Xenopus securin that inhibits chromatid separation, is overexpressed in many human tumor types, and mediates transcriptional activation. Loss of yeast securin Pds1p or Drosophila securin pimples is lethal. Here we show that mice lacking PTTG (PTTG -/-) are, surprisingly, viable and fertile; but they have testicular and splenic hypoplasia, thymic hyperplasia, and thrombocytopenia. PTTG -/- mouse embryo fibroblasts exhibited aberrant cell cycle progression with prolonged G2-M phase and binucleated and multinucleated nuclei with increased aneuploidy. PTTG -/- mouse embryo fibroblast metaphases contained quadriradial, triradial, and chromosome breaks, as well as premature centromere division. The results show that PTTG functions to maintain chromosome stability, cell cycle progression, and appropriate cell division. Moreover, mammalian sister chromatid separation, an important transition in the cell cycle, is likely regulated by mechanisms in addition to securin.//////////////////