| phosphatase and tensin homolog | OKDB#: 1793 |
| Symbols: | PTEN | Species: | human | ||
| Synonyms: | BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del, PTENbeta | Locus: | 10q23.31 in Homo sapiens |
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| General Comment |
Activation of dormant ovarian follicles to generate mature eggs. Li J et al. Although multiple follicles are present in mammalian ovaries, most of them remain dormant for years or decades. During reproductive life, some follicles are activated for development. Genetically modified mouse models with oocyte-specific deletion of genes in the PTEN-PI3K-Akt-Foxo3 pathway exhibited premature activation of all dormant follicles. Using an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, we found that short-term treatment of neonatal mouse ovaries increased nuclear exclusion of Foxo3 in primordial oocytes. After transplantation under kidney capsules of ovariectomized hosts, treated follicles developed to the preovulatory stage with mature eggs displaying normal epigenetic changes of imprinted genes. After in vitro fertilization and embryo transfer, healthy progeny with proven fertility were delivered. Human ovarian cortical fragments from cancer patients were also treated with the PTEN inhibitor. After xeno-transplantation to immune-deficient mice for 6 months, primordial follicles developed to the preovulatory stage with oocytes capable of undergoing nuclear maturation. Major differences between male and female mammals are unlimited number of sperm and paucity of mature oocytes. Thus, short-term in vitro activation of dormant ovarian follicles after stimulation of the PI3K-Akt pathway allows the generation of a large supply of mature female germ cells for future treatment of infertile women with a diminishing ovarian reserve and for cancer patients with cryo-preserved ovaries. Generation of a large number of human oocytes also facilitates future derivation of embryonic stem cells for regenerative medicine.////////Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Kawamura K 2013 et al.
Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.
/////////////////////////In Vitro Activation of Follicles and Fresh Tissue Auto-transplantation in Primary ovarian insufficiency Patients. Zhai J et al. (2016) Recently, two Primary ovarian insufficiency (POI) patients delivered healthy babies after IVA (In Vitro Activation) treatment followed by auto-transplantation of frozen-thawed ovarian tissues. To report the first case of live birth after IVA treatment following fresh ovarian tissue grafting in POI patients, together with monitoring of follicle development and serum hormonal changes. Prospective observational cohort study. We performed IVA treatment in 14 POI patients with mean age of 29 years, mean duration since last menses of 3.8 years, and average basal FSH level of 94.5 mIU/mL. Prior to IVA treatment, all patients received routine hormonal treatments with no follicle development. We removed one ovary from POI patients and treated them with Akt stimulators. We improved upon early procedures by grafting back fresh tissues using a simplified protocol. In six of the 14 patients (43%), a total of 15 follicle development waves were detected, and 4 patients had successful oocyte retrieval to yield 6 oocytes. For 2 patients showing no spontaneous follicle growth, HMG treatment induced follicle growth at 6-8 months after grafting. After IVF of oocyte retrieved, 4 early embryos were derived. Following embryo transfer, one patient became pregnant and delivered a healthy baby boy, with three other embryos under cryopreservation. IVA technology can effectively activate residual follicles in some POI patients and allow them to conceive their own genetic offspring. IVA may also be useful for treating patients with ovarian dysfunction including aging women and cancer survivors.//////////////////
The Safe Use of a PTEN Inhibitor for the Activation of Dormant Mouse Primordial Follicles and Generation of Fertilizable Eggs. Adhikari D et al. Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF) patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF). There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activationWe have recently reported that PTEN (phosphatase and tensin homolog deleted on chromosome ten) prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. To study the safety and efficacy of the use of such inhibitors, we activated primordial follicles from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic). These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer.
RESULTS AND CONCLUSIONS:
Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses. Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques. ////////Ovary transplantation: to activate or not to activate. Kawamura K et al. (2015)//////////////////In Vitro Activation: A Dip Into the Primordial Follicle Pool? Yin O et al. (2016) A current limitation of assisted reproduction is the number of available female gametes. This Commentary discusses in vitro activation (IVA), a technique that activates dormant ovarian follicles so that these follicles can become mature oocytes for fertilization. There is considerable evidence that mechanical signaling plays an important role in oocyte maturation and survival; manipulation of the mechanical environment is a key component of the IVA process. IVA acts on existing follicles and does not promote neo-oogenesis, which likely contributes little to the primordial follicle pool in the adult. Several women with primary ovarian insufficiency who underwent the IVA procedure have achieved live births. IVA might also be applicable to women with pathological diminished ovarian reserve and those with physiological diminished reserve due to natural aging. Cancer patients with cryopreserved ovarian tissue also might benefit from IVA. Based on future studies, IVA could prove to be a revolutionary tool for assisted reproduction./////////////////Activation of dormant follicles: a new treatment for premature ovarian failure? Kawamura K et al. (2016) Premature ovarian failure (POF) is diagnosed by amenorrhea before 40 years of age. Owing to exhaustion of follicles in POF ovaries, egg donation is the only option. Although menstrual cycles cease in POF patients, some of them still contain residual dormant follicles in ovaries. Recently, we developed a new infertility treatment and named it as in-vitro activation (IVA), which enables POF patients to conceive using their own eggs by activation of residual dormant follicles. Here, we summarize data showing the potential of IVA as a new infertility treatment for POF patients. Transgenic mouse studies revealed that the stimulation of phosphatidylinositol-3-kinase-AKT-forkhead box O3 pathway activated dormant primordial follicles. In murine and human ovaries, the phosphatase and tensin homolog inhibitors and phosphatidylinositol-3-kinase activators were demonstrated to activate dormant primordial follicles in in-vitro cultures. Subsequent studies showed that ovarian fragmentation suppressed Hippo signaling pathway, leading to ovarian follicle growth. Combining these two methods in an IVA approach followed by ovarian tissue autotransplantation, successful follicle growth, and pregnancies were reported in POF patients. Currently, two healthy babies were delivered, together with two additional pregnancies. IVA treatment is a potential infertility therapy for POF patients who have residual follicles.//////////////////Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency. Huhtaniemi I et al. (2018) Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.//////////////////
NCBI Summary: This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015] |
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| General function | Intracellular signaling cascade, Cell cycle regulation, Tumor suppressor, Enzyme | ||||
| Comment | The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation. Zhang J et al. (2019) Cullin ring-finger ubiquitin ligase 4 (CRL4) has multiple functions in the maintenance of oocyte survival and meiotic cell cycle progression. DCAF13, a novel CRL4 adaptor, is essential for oocyte development. But the mechanisms by which CRL4-DCAF13 supports meiotic maturation remained unclear. In this study, we demonstrated that DCAF13 stimulates the meiotic resumption-coupled activation of protein synthesis in oocytes, partially by maintaining the activity of PI3K signaling pathway. CRL4-DCAF13 targets the polyubiquitination and degradation of PTEN, a lipid phosphatase that inhibits PI3K pathway as well as oocyte growth and maturation. Dcaf13 knockout in oocytes caused decreased CDK1 activity and impaired meiotic cell cycle progression and chromosome condensation defects. As a result, chromosomes fail to be aligned at the spindle equatorial plate, the spindle assembly checkpoint is activated, and most Dcaf13 null oocytes are arrested at the prometaphase I. The DCAF13-dependent PTEN degradation mechanism fits in as a missing link between CRL4 ubiquitin E3 ligase and PI3K pathway, both of which are crucial for translational activation during oocyte GV-MII transition.////////////////// Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice. Chang EM et al. (2015) Cisplatin is a first-line chemotherapeutic agent for ovarian cancer that acts by promoting DNA cross links and adduct. However drug resistance and considerable side effects including reproductive toxicity remain a significant challenge. PTEN is well known as a tumor suppressor function which plays a fundamental role in the regulation of the cell cycle, apoptosis and development of cancer. At the same time PTEN has been revealed to be critically important for the maintenance of the primordial follicle pool. In this study, we investigated the role of PTEN/Akt/FOXO3 pathway in cisplatin-induced primordial follicle depletion. Cisplatin induced ovarian failure mouse model was used to evaluate how this pathway involves. In vitro maturation was used for oocyte rescue after cisplatin damage. We found that cisplatin treatment decreased PTEN levels, leading to a subsequent increase in the phosphorylation of key molecules in the pathway. The activation of the PTEN/Akt/FOXO3 pathway cascade increased cytoplasmic translocation of FOXO3a in cisplatin-treated follicles, which in turn increased the pool size of growing follicles, and rapidly depleted the number of dormant follicles. Once activated, the follicles were more prone to apoptosis, and their cumulus cells showed a loss of luteinizing hormone (LH) receptor expression, which leads to failure during final maturation and ovulation. In vitro maturation to rescue oocytes in a cisplatin-treated mouse model resulted in successful maturation and fertilization. This study is the first to show the involvement of the PTEN/Akt/FOXO3 pathway in premature ovarian failure after cisplatin treatment and the possibility of rescue through in vitro maturation.////////////////// Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles. Kim SY et al. (2015) In this study, we explored the effects of oocytic phosphoinositide 3-kinase (PI3K) activation on folliculogensis by generating transgenic mice, in which the oocyte-specific Cre-recombinase induces the expression of constitutively active mutant PI3K during the formation of primordial follicles. The ovaries of neonatal transgenic (Cre+) mice showed significantly reduced apoptosis in follicles, which resulted in an excess number of follicles per ovary. Thus, the elevation of phosphatidylinositol (3,4,5)-trisphosphate levels within oocytes promotes the survival of follicles during neonatal development. Despite the increase in AKT phosphorylation, primordial follicles in neonatal Cre+ mice remained dormant demonstrating a nuclear accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). These primordial follicles containing a high level of nuclear PTEN persisted in postpubertal females, suggesting that PTEN is the dominant factor in the maintenance of female reproductive lifespan through the regulation of primordial follicle recruitment. Although the oocytic PI3K activity and PTEN levels were elevated, the activation of primordial follicles and the subsequent accumulation of antral follicles with developmentally competent oocytes progressed normally in prepubertal Cre+ mice. However, mature Cre+ female mice were anovulatory. Because postnatal day 50 Cre+ mice released cumulus-oocyte complexes with developmentally competent oocytes in response to super-ovulation treatment, the anovulatory phenotype was not due to follicular defects but rather endocrine abnormalities, which were likely caused by the excess number of overgrown follicles. Our current study has elucidated the critical role of oocytic PI3K activity in follicular function, as well as the presence of a PTEN-mediated mechanism in the prevention of immature follicle activation.////////////////// Short-Term PTEN Inhibition Improves In Vitro Activation of Primordial Follicles, Preserves Follicular Viability, and Restores AMH Levels in Cryopreserved Ovarian Tissue From Cancer Patients. Novella-Maestre E et al. (2015) In vitro activation and growth of primordial dormant follicles to produce fertilizable oocytes would provide a useful instrument for fertility preservation. The employment of Phosphatase and TENsin homolog (PTEN) inhibitors, in combination with Protein kinase B (Akt) stimulating molecules, has been previously employed to increase follicular activation through the stimulation of the PTEN-Akt pathway. We aim to establish improved in vitro activation also for cancer patients whose ovarian tissue has already been cryopreserved. Fresh and previously cryopreserved human ovarian cortex were exposed to short-term, low-concentration and ovary-specific treatment with only a PTEN inhibitor. Our in vitro activation protocol enhances the activation mechanisms of primordial follicles in both fresh and cryopreserved samples, and enlarges growing populations without inducing apoptosis in either follicles or the surrounding stroma. Treatment augments estradiol secretion and restores the expression levels of the previously diminished Anti-Müllerian hormone by means of cryopreservation procedures. Genomic modulation of the relative expression of PTEN pathway genes was found in treated samples. The in vitro activation protocol offers new alternatives for patients with cryopreserved tissue as it increases the pool of viable activated follicles available for in vitro growth procedures. The combination of ovarian tissue cryopreservation and in vitro activation of primordial follicles, the main ovarian reserve component, will be a major advancement in fertility preservation.////////////////// Inhibition of phosphatase and tensin homolog (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles. McLaughlin M 2014 et al. In the mammalian ovary a small number of follicles are steadily recruited from the quiescent pool to undergo development. Follicle loss, maintenance and growth are strictly controlled by complex molecular interactions including the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway. Stimulation of PI3K promotes phosphorylation of Akt resulting in follicle survival and activation of growth whereas this pathway is suppressed by the actions of the phosphatase and tensin homolog (PTEN). The aim of this study was to determine the effect of dipotassium bisperoxo(5-hydroxypyridine-2-carboxyl)oxovanadate (bpV), a reversible inhibitor of PTEN, on the activation, survival and development of human ovarian follicles in vitro. Biopsied ovarian tissue fragments were obtained from 17 women aged 23-46 years and exposed to 1 ?M bpV(HOpic) (n=146) or control medium (n=128) for 24 h. Media were then replaced with control medium and all tissue incubated for a further 5 days. Ovarian tissue from each treatment group was fixed after the initial 24 h culture period and phosphorylated Akt was quantified by western blotting. After 6 days incubation all tissue fragments were inspected under light microscopy and any secondary follicles =100 ?m isolated. Isolated follicles were cultured individually in control medium supplemented with 100 ng/ml recombinant human activin A. Tissue fragments without follicles suitable for isolation were fixed and processed for histological and immunohistochemical analysis. During 6 days culture, follicle activation occurred in tissue samples from both treatment groups but with significantly more follicles progressing to the secondary stage of development in the presence of 1 ?M bpV(HOpic) compared to control (31% vs 16%; p<0.05). Increased activation was associated with increased Akt phosphorylation and increased nuclear export of FOXO3. However isolated and cultured follicles that had been exposed to bpV(HOpic) showed limited growth and reduced survival compared to follicles from control fragments (p <0.05). This study demonstrates that inhibition of PTEN with bpV(HOpic) affects human ovarian follicle development by promoting the initiation of follicle growth and development to the secondary stage, as in rodent species, but severely compromises the survival of isolated secondary follicles. ///////////////////////// 214 SUPEROVULATION IN A/J MICE USING A COMBINATION OF GONADOTROPINS AND THE PTEN INHIBITOR bpV(pic). Suzuki O 2013 et al. Strain and individual differences in superovulation constitute a serious problem in mice. Gonadotropins stimulate the maturation of developing ovarian follicles, but not primordial follicle activation (PFA), which is negatively controlled by the Phosphatase and Tensin Homologue Deleted from Chromosome 10 (PTEN). PTEN inhibitors may increase the number of developing follicles by promoting PFA. If so, subsequent gonadotropin injections may make more follicles ovulate. This study tested whether PTEN inhibitors promote superovulation by gonadotropins and examined the fertilizability of ovulated oocytes in vitro. Method: Immature females of the low responder A/J mouse strain were used. Based on preliminary results regarding peaks in the daily changes in the ovary weight/body weight ratio and ovarian anti-M?an hormone protein content after injections of the PTEN inhibitor, dipotassium bisperoxo (picolinato) oxovanadate (V) bpV(pic), the number of ovulated oocytes was examined using four combinations of the bpV(pic) dose and interval between the bpV(pic) and pregnant mare serum gonadotropin (PMSG) injections: 1) 3?g and PMSG on Day 3; 2) 3?g and PMSG on Day 4; 3) 30?g and PMSG on Day 1; and 4) 30?g and PMSG on Day 2. Ovulation was induced by hCG 48h after PMSG injection. In vitro fertilization of the obtained oocytes was performed using TYH medium and epididymal sperm from adult ICR male mice (Day 1). Subsequently, the oocytes were cultured in KSOMaa+0.1% bovine serum albumin for 4 days. The numbers of two-cell embryos and blastocysts were recorded on Days 2 and 5, respectively. Results: The average number of oocytes collected in treatments 1 to 4 was 1) 7.2?0.7 v. 9.4?1.6 ,control v. bpV(pic), mean?s.e.m., , 2) 7.8?0.7 v. 9.0?1.4; 3) 9.8?1.6 v. 11.2?1.0; and 4) 9.4?1.0 v. 7.4?1.9. More oocytes tended to be collected in the bpV(pic) groups in treatments 1 to 3, but the differences were not significant on ANOVA. The corresponding percentages of two-cell embryos on Day 2 after insemination were 1) 78.7?7.7% v. 83.7?5.6%; 2) 76.0?4.2% v. 65.2?4.2%; 3) 53.5?13.0% v. 68.6?9.1%; and 4) 78.2?9.7% v. 55.2?5.7%. The respective percentages of blastocysts on Day 5 after insemination were 1) 62.7?6.5% v. 69.5?8.1%; 2) 67.9?7.7% v. 41.6?5.6%; 3) 74.9?11.3% v. 79.2?7.8%; and 4) 78.0?3.8% v. 60.5?4.3%. On weighted ANOVA with angular transformations, the two-cell embryo and blastocyst rates were significantly lower in bpV(pic) groups than in control groups for treatments 2 and 4. Discussion: More oocytes tended to be collected in the bpV(pic) groups in 3 of the 4 experimental treatments. Different injection intervals between bpV(pic) and PMSG influenced both the superovulation efficiency and fertilizability of the oocytes. This new method using both PTEN inhibitors and gonadotropins is a promising method for improving superovulation efficiency, although the optimal injection scheme should be determined. ///////////////////////// A role for C. elegans Eph RTK signaling in PTEN regulation. Brisbin S et al. PTEN is one of the most commonly lost tumor suppressors in human cancer and is known to inhibit insulin signaling. Eph receptor tyrosine kinases (RTKs) have also been implicated in cancer formation and progression, and they have diverse functions, including nervous and vascular system development. We show that in C. elegans, the VAB-1 Eph kinase domain physically interacts with and phosphorylates PTEN (DAF-18), diminishing its protein levels and function. vab-1 mutants show increased longevity and sensitivity to dauer conditions, consistent with increased DAF-18/PTEN activity and decreased insulin-like signaling. Moreover, daf-18 mutations suppress vab-1 oocyte maturation phenotypes independent of PI3K signaling. We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. Possible implications for human cancers are discussed, based on the idea that mutually inhibitory interactions between PTEN and Eph RTKs may be conserved. Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression. Lagu?N et al. The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of FSH, including the PI3K/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Pten(flox/flox);Amhr2(cre/+)). The majority of Pten(flox/flox);Amhr2(cre/+) mice featured no ovarian anomalies, but occasionally ( approximately 7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Pten(flox/flox);Amhr2(cre/+) GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously-occuring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and crosstalk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Pten(flox/flox);Ctnnb1(flox(ex3)/+);Amhr2(cre/+)) resulted in the development of GCT similar to those observed in Pten(flox/flox);Amhr2(cre/+) mice, but with 100% penetrance, perinatal onset, extremely rapid growth, and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT, and provide the first animal models for metastatic GCT. | ||||
| Cellular localization | Cytoplasmic | ||||
| Comment | RNA interference mediated pten knock-down inhibit the formation of polycystic ovary. Ouyang JX et al. Pten (phosphatase and tensin homolog deleted on chromosome 10), a kind of tumor suppressor gene, plays important roles in female reproductive system. But its expression and roles in the formation of polycystic ovaries are yet to be known. In this study, we constructed a rat model of PCOS using norethindrone and HCG injections and found the expressions of pten mRNA and PTEN protein increased significantly in the polycystic ovary tissue by immunohistochemistry, RT-PCR, and western blot. Furthermore, the results showed that in vivo ovaries could be effectively transfected by lentiviral vectors through the ovarian microinjection method and indicated that pten shRNA may inhibit the formation of polycystic ovaries by pten down-regulation. Our study provides new information regarding the role of PTEN in female reproductive disorders, such as polycystic ovary syndrome. | ||||
| Ovarian function | Follicle development, Initiation of primordial follicle growth, Antral follicle growth, Ovulation, Luteinization | ||||
| Comment | Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Suzuki N et al. (2015) Is ovarian tissue cryopreservation using vitrification followed by in vitro activation (IVA) of dormant follicles a potential approach for infertility treatment of patients with primary ovarian insufficiency (POI)? Our vitrification approach followed by IVA treatment is a potential infertility therapy for POI patients whose ovaries contain residual follicles. Akt (protein kinase B) stimulators PTEN (phosphatase with TENsin homology deleted in chromosome 10) inhibitor and phosphatidyinositol-3-kinase (PI3 kinase) stimulator] activate dormant primordial follicles in vitro and ovarian fragmentation disrupts the Hippo signaling pathway, leading to the promotion of follicle growth. We treated POI patients with a combination of ovarian vitrification, fragmentation and drug treatment, followed by auto-transplantation, and reported successful follicle growth and pregnancies. Prospective clinical study of 37 infertile women with POI between 12 August 2011 and 1 November 2013. We enrolled 10 new patients since the previous publication. POI patients were originally selected based on a history of amenorrhea for more than 1 year and elevated serum FSH levels of >40 mIU/ml (n = 31) but this was later changed to >4 months, age <40 years and serum FSH levels of >35 mIU/ml (n = 6) (mean 71.8 ± 30.8, range 35.5-197.6) so as to include patients with a shorter duration of amenorrhea. Under laparoscopic surgery, ovariectomy was performed and ovarian cortices were dissected into strips for vitrification. Some pieces were examined histologically. After warming, two to three strips were fragmented into smaller cubes before culturing with Akt stimulators for 2 days. After washing, ovarian cubes were transplanted beneath the serosa of Fallopian tubes under laparoscopic surgery. Follicle growth was monitored by ultrasound and serum estrogen levels. After oocyte retrieval from mature follicles, IVF was performed. Among 37 patients, 54% had residual follicles based on histology. Among patients with follicles, 9 out of 20 showed follicle growth in auto-grafts with 24 oocytes retrieved from six patients. Following IVF and embryo transfer into four patients, three pregnancies were detected based on serum hCG, followed by one miscarriage and two successful deliveries. For predicting IVA success, we found that routine histological analyses of ovarian cortices and shorter duration from initial POI diagnosis to ovariectomy are valid parameters. Although our findings suggest that the present vitrification protocol is effective for ovarian tissue cryopreservation, we have not compared the potential of vitrification and slow freezing in follicle growth after grafting. We chose the serosa of Fallopian tubes as the auto-grating site due to its high vascularity and the ease to monitor follicle growth. Future studies are needed to evaluate the best auto-grafting sites for ovarian tissues. Also, future studies are needed to identify biological markers to indicate the presence of residual follicles in POI to predict IVA treatment outcome. In POI patients, ovarian reserve, namely the pool of residual follicles, continues to diminish with age. If one ovary is cryopreserved at an earlier stage of POI, patients could undergo additional non-invasive infertility treatments before the final decision for the IVA treatment. Furthermore, in the cases of unmarried POI patients, cryopreservation of ovarian tissues allows their fertility preservation until they desire to bear children. This work was supported by Grant-In-Aid for Scientific Research (Research B: 24390376, Challenging Exploratory Research: 24659722, and Innovative Areas, Mechanisms regulating gamete formation in animals: 26114510) and by research funds from the Smoking Research Foundation, and the Takeda Science Foundation. None of the authors has a conflict of interest. UMIN000010828.//////////////////The effect of bpV(HOpic) on in vitro activation of primordial follicles in cultured swine ovarian cortical strips. [Raffel N et al. (2019) The vanadate-derivative dipotassium bisperoxo (5-hydroxy-pyridine-2-carboxylic) oxovanadate (V) (bpV(HOpic)), a pharmacological inhibitor of phosphatase and tensin homolog (PTEN), has been used in ovarian follicle culture systems for activation of follicular growth in vitro and suggested to be responsible for primordial follicle survival through indirect Akt activation. For pig ovarian tissue, it is still not clear which culture medium needs to be used, as well as which factors and hormones could influence follicular development; this also applies to bpV(HOpic) exposure. Therefore, ovarian cortical strips from pigs were cultured in 1 µM bpV(HOpic) (N=24) or control medium (N=24) for 48 h. Media were then replaced with control medium and all tissue pieces incubated for additional 4 days. The strips were embedded in paraffin for histological determination of follicle proportions at the end of the culture period and compared to histological sections from tissue pieces without cultivation, which had been embedded right after preparation; comparison of healthy follicles for each developmental stage was performed to quantify follicle survival and activation. After 6 days culture, follicle activation occurred in tissue samples from both cultured groups but significantly more follicles showed progression of follicular development in the presence of 1 µM bpV(HOpic). The amount of non-vital follicles was not significantly increased during cultivation. BpV(HOpic) affects pig ovarian follicle development by promoting the initiation of follicle growth and development, similar as in rodent species and humans. This article is protected by copyright. All rights reserved.////////////////// | ||||
| Expression regulated by | Steroids, Growth Factors/ cytokines | ||||
| Comment | The effect of androgens on ovarian follicle maturation: Dihydrotestosterone suppress FSH-stimulated granulosa cell proliferation by upregulating PPARγ-dependent PTEN expression. Chen MJ et al. (2015) Intraovarian hyperandrogenism is one of the determining factors of follicular arrest in women with polycystic ovary syndrome (PCOS). Using androgenized rat models, we investigated the effects of androgens on metabolism, as well as on factors involved in follicular arrest and the reduced number of estrus cycles. The dihydrotestosterone (DHT)-treated rats had fewer estrus cycles, higher numbers of large arrested follicles and an increased in body weight gain compared with the dehydroepiandrostenedione (DHEA)- and placebo-treated rats. In cultured rat granulosa cells, DHT suppressed follicle stimulating hormone (FSH)-induced granulosa cell proliferation and increased the accumulation of cells in the G2/M phase. DHT decreased phosphorylated Akt (p-Akt) and cyclin D1 levels through increasing PTEN. DHT-promoted PTEN expression was regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in granulosa cells. Meanwhile, in the large follicles of the DHT-treated rats, the expressions of PPARγ and PTEN were higher, but the expression of p-Akt and proliferating cell nuclear antigen (PCNA) were lower. Conclusively, DHT and DHEA produced differential effects on metabolism in prepubertal female rats like clinical manifestations of women with PCOS. DHT treatment may affect ovarian follicular maturation by altering granulosa cell proliferation through the regulation of enhancing PPARγ dependent PTEN/p-Akt expression in the granulosa cells.////////////////// Insulin attenuates IGF-1-Akt pathway, not IGF-1-ERK pathway, in luteinized granulosa cells with an increase in PTEN. Iwase A et al. Context: Insulin resistance is considered as part of the pathogenesis of polycystic ovary syndrome (PCOS) and PCOS patients often show hyperinsulinemia. The influence of insulin on folliculogenesis in women with PCOS has not been fully investigated. Objective: To assess the induction of PTEN expression with insulin treatment and effects of PTEN on IGF-1-induced granulosa cell proliferation as well as the correlation of PTEN levels with the concentration of insulin in follicular fluid in PCOS and non-PCOS patients. Design, Setting, Patients and Main Outcome Measures: A cell proliferation assay, real-time RT-PCR and Western blotting for PTEN, Akt and ERK1/2 were conducted in primary cultured granulosa cells under IGF-1 stimulation with or without insulin pretreatment. Phosphorylation of Akt and ERK1/2 was also determined by Western blotting. We also measured the insulin concentration in follicular fluid and the levels of PTEN expression in granulosa cells collected at the time of oocyte retrieval of IVF in PCOS (n =13) and non-PCOS patients (n =37). Results: PTEN expression was induced by insulin. Pretreatment with insulin attenuated the IGF-1-induced Akt phosphorylation and cell proliferation, but not ERK1/2 phosphorylation. A PI3K inhibitor, LY294002, inhibited the IGF-1-induced cell proliferation. Suppression of insulin-induced PTEN expression using siRNA recovered IGF-1-induced Akt phosphorylation. PTEN levels in granulosa cells, which tended to be higher in PCOS patients, were correlated with the insulin concentration in follicular fluid. Conclusions: PTEN may influence the proliferation of human granulosa cells as well as disturbance of follicular growth in PCOS patients. | ||||
| Ovarian localization | Primordial Germ Cell, Oocyte, Granulosa, Theca, Luteal cells, Ovarian tumor | ||||
| Comment | Formation of Primordial Follicles and Immunolocalization of PTEN, PKB and FOXO3A Proteins in the Ovaries of Fetal and Neonatal Pigs. Ding W et al. The assembly of primordial follicles and subsequent development and transition of the primordial follicle to the primary follicle are critical processes in ovarian biology. In order to examine follicle formation and development in fetal and neonatal pigs, ovarian samples were obtained from a famous local breed of Chinese pigs, Erhualian pigs, ranging in age from 50 days postcoitum to 1 day postpartum in our current study. Morphological changes in the ovaries of the fetal and neonatal pigs indicated that egg nests were the earliest recognizable gamete cells. The proportion of egg nests decreased from 98.4 to 25.6% and the proportion of single follicles increased from 1.6 to 74.4% between 70 and 90 days postcoitum. The proportions of primordial follicles increased between 70 and 90 days postcoitum but decreased from 90 days postcoitum to 1 day postpartum. Our results suggested that the key stage of primordial follicle formation was between 70 and 90 days postcoitum and that the major stage of transition from primordial follicles into primary follicles was between 90 days postcoitum and 1 day postpartum. Experiments were also conducted to examine the localization of PTEN, PKB and FOXO3A proteins in the porcine ovaries by immunohistochemistry and immunoblotting. The results indicated that PTEN, PKB and FOXO3A were localized in the germ cells of egg nests, cytoplasm of oocytes and granulosa cells of follicles ranging from the primordial to secondary stages and that the staining intensity was weak in granulosa cells but strong in oocytes. The different staining patterns of PTEN, FOXO3A and PKB suggested that these proteins were expressed in a stage- and cell-specific manner during ovarian follicle formation and development in the fetal and neonatal pig. PTEN expression in ovine granulosa cells increases during terminal follicular growth Froment P, et l . In the present paper, we have studied the expression of the Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) and its putative biological role in the sheep ovary. We found by Northern-blot, immunohistochemistry and immunoblot that PTEN is highly expressed in granulosa cells from large differentiated follicles (LF) in comparison with small proliferating follicles (SF) (P<0.001), with no clear effect of follicle quality. Moreover, the PTEN lipid phosphatase activity is also higher in LF than in SF (P<0.01). In contrast, levels of the phosphorylated form of AKT (pAKT) are lower in LF than in SF (P<0.0001). IGF-I and insulin but not FSH, LH or forskolin are able to stimulate the expression of PTEN mRNA (P<0.001) and protein by ovine granulosa cells after 48h of culture in vitro. An IGF-1 time course analysis showed that expression of PTEN protein appeared after 12h of culture, concomitant with the fall of the pAKT levels, which peaked after 6h of stimulation with IGF-I. Moreover, transfection experiments showed that overexpression of PTEN in ovine granulosa cells induced a decrease and an increase in E2F and p27 promoter activity, respectively (P<0.05). Overall, our present data show for the first time that the expression of PTEN increases during terminal follicular growth. This increase, that might be induced by IGF-I but not FSH, would participate in the proliferation/differentiation transition of ovine granulosa cells in differentiating follicles. IGF-1-induced Akt phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells. Goto M et al. Granulosa cells proliferate and then undergo differentiation, an inverse relationship between these processes being observed during terminal follicular growth. During terminal follicular growth and initial luteinization, there is a necessary transition of granulosa cells to a less proliferative and highly steroidogenic form in response to luteinizing hormone (LH). Although the expression of several molecules has been reported to be up-regulated by LH, proliferation/differentiation transition is not fully understood. Here, we show that the expression of a tumor suppressor, Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was induced with human chorionic gonadotropin (hCG) treatment in human luteinized granulosa cells. Pretreatment with hCG attenuated insulin-like growth factor (IGF)-I-induced phosphorylation of Akt and cell proliferation, not phosphorylation of ERK1/2. Moreover, suppression of hCG-induced PTEN expression with siRNA increased Akt phosphorylation and cell proliferation in response to IGF-1. We also demonstrate that a PI3K inhibitor, LY294002, not a MEK inhibitor, PD98059, inhibited IGF-1-induced cell proliferation. In conclusion, PTEN induced to express by hCG in luteinized granulosa cells inactivates Akt, not ERK, and attenuates IGF-1-induced cell proliferation. PTEN expression may be a trigger for proliferation/differentiation transition in human granulosa cells. Mutations of the KIT gene and loss of heterozygosity of the PTEN region in a primary malignant melanoma arising from a mature cystic teratoma of the ovary. Tate G et al. A tumor suppressor gene at 10q23.3, designated PTEN, encoding a dual-specificity phosphatase with lipid and protein phosphatase activity, has been shown to play a pivotal role in the pathogenesis of a variety of human cancers. A frequent loss of heterozygosity (LOH) at 10q is found in melanoma; however, little is known about the role of PTEN in the pathogenesis of a primary malignant melanoma derived from ovarian mature cystic teratoma, which is an extremely rare melanoma. This study examined the genetic alterations involved in the mitogen-activated protein kinase and phosphatidylinositol 3 kinase pathways in an ovarian malignant melanoma. A LOH analysis revealed hemizygous deletion around and in the PTEN gene not only in the ovarian melanoma but also in a mature cystic teratoma. Another case of ovarian mature cystic teratomas in the absence of melanoma also showed allelic loss of the PTEN region. To date, mutations of BRAF, NRAS, and KIT genes have been reported in malignant melanomas. In the present study, D816H and K558E mutations of the KIT gene were revealed in the melanoma arising from a mature cystic teratoma, but not in a mature cystic teratoma. No mutations of the BRAF and NRAS genes were found in the melanoma. These results indicate that LOH of the PTEN region is one of the molecular alterations of an ovarian mature cystic teratoma and a KIT mutation is an additional promotional event associated with the oncogenesis of a melanoma arising from an ovarian mature cystic teratoma. Expression status and mutational analysis of the PTEN and P13K subunit genes in ovarian granulosa cell tumors. Bittinger S et al. Granulosa cell tumors (GCT) are a unique subset of ovarian tumors which have a molecular phenotype resembling that of follicle stimulating hormone (FSH)-stimulated pre-ovulatory granulosa cells. FSH acts via its receptor to stimulate signaling pathways including the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Activation of this pathway occurs in solid tumors, including ovarian epithelial tumors, through mutation of the PI3K subunit genes or inactivation of the tumor suppressor, PTEN. Activation of this pathway would be predicted to be tumorigenic in granulosa cells.Expression of the 2 PI3K subunit genes, PIK3CA, which encodes the catalytic subunit, and PIK3R1, which encodes the regulatory subunit, together with the PTEN gene was determined in a panel of GCT, 2 human GCT-derived cell lines, COV434 and KGN, and normal ovary. Direct sequence analysis was used to screen for mutations. Expression of all 3genes was observed in the GCT without evidence of overexpression for the PI3K subunit genes or loss of expression for PTEN. Sequence analysis of amplicons spanning exons 9and 20, in which greater than 75% of mutations occur in the PIK3CA gene did not identify any missense mutations. Similarly, the previously reported deletions in exons 12 and 13 of the PIK3R1 were not found in the GCT. Three amplicons spanning the entire coding sequence of the PTEN gene were sequenced; neither deletions nor mutations were identified.These findings suggest that activation of PI3K signaling through PI3K/PTEN mutation or altered expression, in contrast to many other types of solid tumor, is not associated with GCT. | ||||
| Follicle stages | Primary, Secondary, Antral, Preovulatory | ||||
| Comment | PTEN and Akt expression during growth of human ovarian follicles. Goto M et al. PURPOSE: To assess the expression of PTEN and total and phosphorylated Akt in human ovarian follicles during follicular growth. METHODS: Immunohistochemistry of ovarian tissues and Western blotting and immunofluorescence of primary cultured luteinized granulosa cells for PTEN and Akt. RESULTS: Immunoreactivity of Akt was found in the oocytes, granulosa cells and theca cells in primordial follicles, follicles at each growing stage and luteal cells. As the follicles grew, staining for PTEN became intense in the granulosa cells, whereas the intensity of phospho-Akt became weak. Western blotting and immunofluorescence analysis using primary cultured granulosa-lutein cells showed Akt and PTEN expression, and phosphorylation of Akt in vitro. CONCLUSIONS: PTEN and Akt are present in the granulosa cells during folliculogenesis. An increase in PTEN may lead to changes in proliferation and/or differentiation of granulosa cells during follicular growth via regulation of Akt phosphorylation. | ||||
| Phenotypes | |||||
| Mutations |
11 mutations
Species: mouse
Species: mouse
Species: human
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: human
Species: mouse
Species: mouse
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | May 7, 2003, 1:12 p.m. | by: |
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| last update: | March 29, 2020, 4:43 p.m. | by: | hsueh email: |
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