Ambrosini et al. (1997) isolated a cDNA encoding an inhibitor of apoptosis (IAP) protein, which they termed survivin. Survivin, also termed API4, encodes a deduced 142-amino acid protein. Sequence analysis revealed that survivin lacks a signal peptide and a hydrophobic domain for membrane insertion. Unlike other IAPs, survivin contains only 1 copy, rather than 2 or 3, of the baculovirus IAP repeat cys/his-based zinc finger, which is essential for apoptosis inhibition
NCBI Summary:
This gene is a member of the inhibitor of apoptosis (IAP) gene family, which encode negative regulatory proteins that prevent apoptotic cell death. IAP family members usually contain multiple baculovirus IAP repeat (BIR) domains, but this gene encodes proteins with only a single BIR domain. The encoded proteins also lack a C-terminus RING finger domain. Gene expression is high during fetal development and in most tumors, yet low in adult tissues. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2011]
General function
Cell death/survival, Anti-apoptotic
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Follicle atresia, Oocyte maturation, Early embryo development
Comment
Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5. MacDonald JA et al. (2018) Cellular metabolic changes that accompany malignant transformation have been heralded as hallmark features of cancer. However, metabolic signatures between neoplasms can be unique, allowing for distinctions in malignancy, invasion and chemoresistance between cancer types and subtypes. Mitochondria are central metabolic mediators, as cellular bioenergetics veers from oxidative phosphorylation to glycolysis. Herein, we evaluate the role of mitochondria in maintenance of cellular metabolism, proliferation, and survival in the adult granulosa tumor cell line, KGN, as well as three epithelial ovarian cancer cell lines to determine distinctions in specific features. Notably, KGN cells were susceptible to TRAIL- and cisplatin-induced death following pretreatment with the metabolic inhibitor FCCP, but not oligomycin A. Collapse of mitochondrial membrane potential was found concomitant with cell death via apoptosis, independent from extrinsic canonical apoptotic routes. Rather, treatment with FCCP resulted in elevated cytochrome c release from mitochondria and decreased responsiveness to BIRC5. Following knockdown of BIRC5, mitochondrial membrane depolarization further sensitized KGN cells to induction of apoptosis via TRAIL. These results indicate an essential role, distinct from metabolism, for mitochondrial membrane potential in KGN cells to sense and respond to external mediators of apoptotic induction.//////////////////
Live imaging RNAi screen reveals genes essential for meiosis in mammalian oocytes. Pfender S et al. (2015) During fertilization, an egg and a sperm fuse to form a new embryo. Eggs develop from oocytes in a process called meiosis. Meiosis in human oocytes is highly error-prone, and defective eggs are the leading cause of pregnancy loss and several genetic disorders such as Down's syndrome. Which genes safeguard accurate progression through meiosis is largely unclear. Here we develop high-content phenotypic screening methods for the systematic identification of mammalian meiotic genes. We targeted 774 genes by RNA interference within follicle-enclosed mouse oocytes to block protein expression from an early stage of oocyte development onwards. We then analysed the function of several genes simultaneously by high-resolution imaging of chromosomes and microtubules in live oocytes and scored each oocyte quantitatively for 50 phenotypes, generating a comprehensive resource of meiotic gene function. The screen generated an unprecedented annotated data set of meiotic progression in 2,241 mammalian oocytes, which allowed us to analyse systematically which defects are linked to abnormal chromosome segregation during meiosis, identifying progression into anaphase with misaligned chromosomes as well as defects in spindle organization as risk factors. This study demonstrates how high-content screens can be performed in oocytes, and allows systematic studies of meiosis in mammals.required to prevent exit from meiosis after anaphase I (Fig. 3e, f), but dispensable for meiotic resumption, progression into anaphase, //////////////////
Expression regulated by
LH
Comment
HCG up-regulates survivin mRNA in human granulosa cells Kumazawa Y,et al .
The apoptosis of granulosa cells is involved in follicular atresia and degeneration of the corpus luteum. The mechanisms that regulate follicular atresia and luteal degeneration remain obscure. Survivin is a member of the family of inhibitors of apoptosis protein that is expressed during fetal development and in cancer tissues. The present study investigates the expression of survivin, as well as its regulation and function in granulosa cells. We identified survivin at the protein level in granulosa cells and detected not only survivin but also splice-variant transcripts in human and mouse granulosa-luteal cells. One-step real-time PCR analysis revealed that HCG increases the amount of survivin mRNA expressed in cultured human granulosa cells. These results suggest that survivin is involved in supporting luteal function, and that HCG contributes to this role.
Ovarian localization
Oocyte, Granulosa, Luteal cells
Comment
Expression of survivin in human oocytes and preimplantation embryos. Balakier H et al. OBJECTIVE: To determine whether survivin is expressed in human oocytes and embryos; embryos grown in?vitro secrete survivin protein; and survivin levels are correlated with embryo cleavage rates. DESIGN: Experimental. Survivin mRNA and protein were expressed during human oocyte maturation, from germinal vesicle to metaphase II stage, and throughout embryo development, from pronuclear stage to blastocyst stage. Survivin was localized predominantly in the cytoplasm of all cells examined and in the oocytes on the chromatin of metaphase chromosomes and midbodies. Western blot analysis of human oocyte and cancer cell extracts detected a full-length (primary) survivin band of 16.5 kDa. Survivin was also detected in conditioned media samples from embryo cultures and showed a positive correlation with embryo cleavage rates. CONCLUSION(S): Our data have demonstrated for the first time that human oocytes/embryos not only express but also secret survivin, suggesting that survivin may play an important role in human oogenesis and embryogenesis.
Expression of antiapoptosis gene survivin in luteinized ovarian granulosa cells of women undergoing IVF or ICSI and embryo transfer: clinical correlations. Varras M et al.BACKGROUND: The purpose of the study was to determine the incidence of survivin gene expression in human granulosa cells during ovarian stimulation in Greek women with normal FSH levels, undergoing IVF or ICSI and to discover any correlation between levels of gene expression and clinical parameters, efficacy of ovulation or outcomes of assisted reproduction. METHODS: Twenty nine women underwent ovulation induction for IVF or ICSI and ET with standard GnRH analogue-recombinant FSH protocol. Infertility causes were male and tubal factor. Cumulus--mature oocyte complexes were denuded and the granulosa cells were analyzed for each patient separately using quantitative reverse transcription polymerase chain reaction analysis for survivin gene expression with internal standard the ABL gene. RESULTS: The ABL and survivin mRNA were detected in granulosa cells in 93.1%. The expression levels of survivin were significantly lower in normal women (male infertility factor) compared to women with tubal infertility factor (p = 0.007). There was no additional statistically significant correlation between levels of survivin expression and estradiol levels or dosage of FSH for ovulation induction or number of dominant follicles aspirated or number of retrieved oocytes or embryo grade or clinical pregnancy rates respectively. CONCLUSIONS: High levels of survivin mRNA expression in luteinized granulosa cells in cases with tubal infertility seem to protect ovaries from follicular apoptosis. A subpopulation of patients with low levels of survivin mRNA in granulosa cells might benefit with ICSI treatment to bypass possible natural barriers of sperm-oocyte interactions. Survivin regulates Plk1 localization to kinetochore in mouse oocyte meiosis. Sun SC et al. Survivin is a member of inhibitors of apoptosis proteins (IAPs), and also belongs to be a member of the chromosomal passenger complex (CPC) which has multiple functions including inhibition of apoptosis and regulation of cell division and SAC activity. Plk1 (polo-like kinase 1) associates with the spindle poles and also distributes to the kinetochores and is shown to involve in spindle organization, APC/C activation and cytokinesis in many models. Our recent work has shown that Survivin is a critical regulator of chromosome segregation and spindle assembly checkpoint (SAC) in meiosis. In the present study, we found that Plk1 co-localized with Survivin at metaphase I (MI) and telophase I (TI) stage after GVBD. Plk1 dispersed into the oocyte cytoplasm or accumulated near the chromosomes after the depletion of Survivin by morpholino (MO) injection. Our results showed that the localization of Plk1 to kinetochores required the involvement of Survivin.
Survivin is a critical regulator of spindle organization and chromosome segregation during rat oocyte meiotic maturation. Wang K et al. SummarySurvivin is a novel member of the inhibitor of apoptosis gene family that bear baculoviral IAP repeats (BIRs), whose physiological roles in regulating meiotic cell cycle need to be determined. Confocal microscopy was employed to observe the localization of survivin in rat oocytes. At the germinal vesicle (GV) stage, survivin was mainly concentrated in the GV. At the prometaphase I (pro-MI) and metaphase I (MI) stage, survivin was mainly localized at the kinetochores, with a light staining detected on the chromosomes. After transition to anaphase I or telophase I stage, survivin migrated to the midbody, and signals on the kinetochores and chromosomes disappeared. At metaphase II (MII) stage, survivin became mainly localized at the kinetochores again. Microinjection of oocytes with anti-survivin antibodies at the beginning of the meiosis, thus blocking the normal function of survivin, resulted in abnormal spindle assembly, chromosome segregation and first polar body emission. These results suggest that survivin is involved in regulating the meiotic cell cycle in rat oocytes.
Perturbation of survivin expression affects chromosome alignment and spindle checkpoint in mouse oocyte meiotic maturation. Sun SC et al. Survivin is a member of inhibitors of apoptosis proteins (IAPs), which have multiple regulatory functions in mitosis, but its roles in meiosis remain unknown. Here, we report its expression, localization and functions in mouse oocyte meiosis. Survivin displayed a maximal expression level in GV stage, and then gradually decreased from Pro-MI to MII stages. Immunofluorescent staining showed that survivin was restricted to the germinal vesicle, associated with centromeres from pro-metaphase I to metaphase I stages, distributed at the midzone and midbody of anaphase and telophase spindles, and located to centromeres at metaphase II stages. Depletion of survivin by antibody injection and morpholino injection resulted in severe chromosome misalignment, precocious polar body extrusion, and larger-than-normal polar bodies. Overexpression of survivin resulted in severe chromosome misalignment and prometaphase I or metaphase I arrest in a large proportion of oocytes. Our data suggest that survivin is required for chromosome alignment and that it may regulate spindle checkpoint activity during mouse oocyte meiosis.
Takai N, et al reported that expression of survivin is associated with malignant potential in epithelial ovarian carcinoma.
They analyzed serial frozen sections for survivin protein expression in 26 patients with ovarian epithelial carcinoma and 10 patients with benign cystadenoma of the ovary by fluorescent immunohistochemistry. Survivin was weakly detected in some benign ovarian cystadenomas (0-12.1%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the epithelial ovarian carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with PCNA-labeling index, clinical stage, histological grade, clinical outcome, and survival rate (p<0.01, respectively). Thus, the survivin protein is a defining diagnostic marker for epithelial ovarian carcinomas that may also yield prognostic information.
Johnson AL, et al reported that survivin is a cell cycle-related and antiapoptotic protein in granulosa cells.
Survivin is a relatively unique member of the inhibitor of apoptosis protein (IAP) family in that it contains a single baculovirus IAP repeat (BIR) domain combined with a COOH-terminal alpha-helix coiled-coil domain instead of the more common zinc-binding RING finger. Results from a variety of transformed or continuous mammalian cell lines suggest that, due to the combination of these features, Survivin is capable of regulating both cell proliferation and apoptotic cell death. However, to date there is essentially no information regarding Survivin expression, regulation or function within the ovary, or in any nonmammalian vertebrate species. In the present studies, cDNAs for chicken (ch) Survivin-142 (homologous to human Survivin-142) plus three alternatively spliced variants (ch Survivin-short, -gamma, and -delta) are described, and of these, transcripts for ch Survivin-142 and -short are expressed in granulosa cells from the hen ovary. Highest levels of Survivin mRNA during follicle development occur in mitotically active granulosa cells from undifferentiated, prehierarchal follicles. Cell cycle analysis determined that Survivin mRNA expression is elevated specifically during the G2/M phase of mitosis. Significantly, transient transfection with ch Survivin-142 in primary cultures of hen granulosa cells attenuates taxol- and N-octanoylsphingosine- (C8-ceramide-) induced caspase-3 activity, whereas overexpression of ch Survivin-short (a truncated variant that lacks much of the functional BIR domain plus the entire alpha-helix coil domain) lacks this antiapoptotic activity. Taken together, these data provide evidence for Survivin in granulosa cells acting as a bifunctional protein associated with regulation of the cell cycle and the inhibition of apoptosis.
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.
Expression of antiapoptosis gene survivin in luteinized ovarian granulosa cells of women undergoing IVF or ICSI and embryo transfer: clinical correlations. Varras M et al. ABSTRACT: BACKGROUND: The purpose of the study was to determine the incidence of survivin gene expression in human granulosa cells during ovarian stimulation in Greek women with normal FSH levels, undergoing IVF or ICSI and to discover any correlation between levels of gene expression and clinical parameters, efficacy of ovulation or outcomes of assisted reproduction. METHODS: Twenty nine women underwent ovulation induction for IVF or ICSI and ET with standard GnRH analogue-recombinant FSH protocol. Infertility causes were male and tubal factor. Cumulus--mature oocyte complexes were denuded and the granulosa cells were analyzed for each patient separately using quantitative reverse transcription polymerase chain reaction analysis for survivin gene expression with internal standard the ABL gene. RESULTS: The ABL and survivin mRNA were detected in granulosa cells in 93.1%. The expression levels of survivin were significantly lower in normal women (male infertility factor) compared to women with tubal infertility factor (p = 0.007). There was no additional statistically significant correlation between levels of survivin expression and estradiol levels or dosage of FSH for ovulation induction or number of dominant follicles aspirated or number of retrieved oocytes or embryo grade or clinical pregnancy rates respectively. CONCLUSIONS: High levels of survivin mRNA expression in luteinized granulosa cells in cases with tubal infertility seem to protect ovaries from follicular apoptosis. A subpopulation of patients with low levels of survivin mRNA in granulosa cells might benefit with ICSI treatment to bypass possible natural barriers of sperm-oocyte interactions.
Follicle stages
Comment
Survivin protein expression in bovine follicular oocytes and their in vitro developmental competence. Jeon K et al. This study examined the relationship between survivin expression and the stage of development of in vitro cultured bovine oocytes and embryos; and whether survivin expression is affected by the quality of cumulus-oocyte complexes (COCS) or the quality of pre-implantation embryos. A polyclonal antibody was prepared using recombinant bovine survivin protein. Expression of survivin mRNA and protein was analyzed by real-time quantitative RT-PCR and immunocytochemistry. In the first experiment, survivin mRNA expression was examined at developmental stages from germinal vesicle (GV) oocyte to blastocyst, it was significantly decreased after fertilization of matured oocytes (P<0.05), then increased slightly to the 8-cell stage followed by rapid increases at the morula and blastocyst stages (P<0.05). In the second experiment, the effect of oocyte quality on survivin protein, pro-apoptotic (bax, caspase-3) and anti-apoptotic (survivin, bax inhibitor) mRNA expression was examined. Survivin protein was more strongly expressed in good quality COCS than in poor quality COCS. The expression of the anti-apoptotic genes, survivin and bax inhibitor, was significantly higher (P<0.05) and that of the pro-apoptotic genes, bax and caspase-3, was significantly lower (P<0.05) in good compared to poor quality COCS. The developmental competence of good quality COCS (30.4% blastocysts) was significantly better than that of poor quality COCS. In the last experiment also, we confirmed that significantly higher expression of survivin and bax inhibitor genes and significantly lower expression of bax and caspase-3 genes was resulted in good quality blastocysts than in poor quality blastocysts (P<0.05). It was concluded that the expression of survivin was related to the quality of COCS, their developmental competence and the quality of in vitro produced blastocysts. Consequently, survivin may be a good candidate marker for embryo quality.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Survivin is essential for fertile egg production and female fertility in mice. Jiang ZZ 2014 et al.
Survivin is the smallest member of the inhibitor of apoptosis protein (IAP) family and acts as a bifunctional protein involved in mitosis regulation and apoptosis inhibition. To identify the physiological role of Survivin in female reproduction, we selectively disrupted Survivin expression in oocytes and granulosa cells (GCs), two major cell types in the ovary, by two different Cre-Loxp conditional knockout systems, and found that both led to defective female fertility. Survivin deletion in oocytes did not affect oocyte growth, viability and ovulation, but caused tetraploid egg production and thus female infertility. Further exploration revealed that Survivin was essential for regulating proper meiotic spindle organization, spindle assembly checkpoint activity, timely metaphase-to-anaphase transition and cytokinesis. Mutant mice with Survivin depleted in GCs showed reduced ovulation and subfertility, caused by defective follicular growth, increased follicular atresia and impaired luteinization. These findings suggest that Survivin has an important role in regulating folliculogenesis and oogenesis in the adult mouse ovary.
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