| v-akt murine thymoma viral oncogene homolog 1 | OKDB#: 999 |
| Symbols: | AKT1 | Species: | human | ||
| Synonyms: | AKT, PKB, RAC, CWS6, PRKBA, PKB-ALPHA, RAC-ALPHA | Locus: | 14q32.33 in Homo sapiens |
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| General Comment |
The AKT oncogene was isolated from the directly transforming murine retrovirus AKT8, which was isolated from an
AKR mouse thymoma cell line. Protein phosphorylation is a fundamental process for the regulation of cellular functions. The coordinated action of both
protein kinases and phosphatases controls the levels of phosphorylation and, hence, the activity of specific target
proteins. One of the predominant roles of protein phosphorylation is in signal transduction, where extracellular signals
are amplified and propagated by a cascade of protein phosphorylation and dephosphorylation events. Two of the best
characterized signal transduction pathways involve the cAMP-dependent protein kinase ) and protein kinase C
(PKC). Each pathway uses a different second-messenger molecule to activate the protein kinase, which, in turn,
phosphorylates specific target molecules. Extensive comparisons of kinase sequences defined a common catalytic
domain, ranging from 250 to 300 amino acids. This domain contains key amino acids conserved between kinases and
are thought to play an essential role in catalysis. Jones et al. (1991) isolated a partial cDNA that encodes a protein
kinase they termed rac (related to the A and C kinases). DNA sequencing identified an open reading frame of 1,440 bp
encoding a protein of 480 amino acids. In an in vitro translation system that used RNA transcribed from cloned cDNAs,
they demonstrated the synthesis of a protein of corresponding size. The predicted protein contained consensus
sequences characteristic of a protein kinase catalytic domain and showed 73 and 68% similarity to protein kinase C and
cAMP-dependent protein kinase, respectively.
NCBI Summary: The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mutations in this gene have been associated with the Proteus syndrome. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2011] |
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| General function | Intracellular signaling cascade, Cell death/survival, Anti-apoptotic | ||||
| Comment | The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor | ||||
| Cellular localization | Cytoplasmic | ||||
| Comment | Genetic and Pharmacological Modulation of Akt1 for Improving Ovarian Graft Revascularization in a Mouse Model. Cohen Y et al. (2015) Ovarian tissue cryopreservation and transplantation is one of a few available treatments for fertility preservation in women diagnosed with cancer. Rapid revascularization is essential for reducing hypoxic damage after grafting and protecting the primordial follicles reserve. Using a mouse model of heterotopic ovarian graft transplantation, we have delineated the role of endothelial Akt1 expression using longitudinal MRI follow-up to quantify angiogenic response. Endothelial Akt1 activation in ovarian grafts promoted angiogenesis to support the graft during post-transplantation hypoxic period. Similarly, simvastatin therapy activated Akt1 at the transplantation site and improved the revascularization and vascular support of ovarian grafts. These results serve as an important first step towards pharmacological intervention to improve revascularization of ovarian grafts and restoration of fertility in cancer survivors. The pro angiogenic effects reported here may extend beyond improving ovarian graft reception in fertility preservation and could potentially be used for different organ or tissue transplantation.////////////////// | ||||
| Ovarian function | Follicle development, Preantral follicle growth, Antral follicle growth, Follicle atresia, Steroid metabolism, Oocyte maturation | ||||
| Comment | IGF1 induces up-regulation of steroidogenic and apoptotic regulatory genes via activation of phosphatidylinositol-dependent kinase/AKT in bovine granulosa cells. Mani AM et al. IGF1, a potent stimulator of cellular proliferation, differentiation and development, regulates granulosa cell steroidogenesis and apoptosis during follicular development. Depending upon species and stage of follicular growth, IGF1 acts on granulosa cell steroidogenesis either alone or together with FSH. We examined the mechanism of action of IGF1 in bovine granulosa cells in serum-free culture without insulin to determine its' potential role in the regulation of steroidogenic and apoptotic regulatory gene expression and to investigate the interaction of FSH with IGF1 on this mechanism. Bovine granulosa cells treated with IGF1 demonstrated a significant increase in 17beta-oestradiol production, cell number and in mRNA expression of CYP11A1, HSD3B1, CYP19A1, BAX, IGF1R and FSHR while FSH alone had no significant effects. IGF1 or FSH alone or both together had no effect on BCL2 expression. IGF1 with FSH resulted in a synergistic increase in granulosa cell number and in mRNA expression of CYP19A1 and IGF1R without altering 17beta-oestradiol production. IGF1 stimulated the PI3K but not the MAPK pathway in granulosa cells, as evidenced by increased phosphorylation of AKT but not ERK-1/2. Addition of the PI3K pathway inhibitor LY294002 (but not the MAPK pathway inhibitor PD98059) abrogated the increased expression of genes induced by IGF1. IGF1 therefore up-regulates the steroidogenic and apoptotic regulatory genes via activation of PI3K/AKT in bovine granulosa cells. The synergistic action of IGF1 with FSH is of likely key importance for the development of small antral follicles before selection; subsequently other factors such as LH may also become necessary for continued cell survival. Akt (protein kinase B) is implicated in meiotic maturation of porcine oocytes. Kalous J et al. The aim of this study was to investigate the involvement of the serine/threonine protein kinase Akt (also called protein kinase B) in the control of meiosis of porcine denuded oocytes (DOs) matured in vitro. Western blot analysis revealed, that the two principal Akt-phosphorylation sites Ser473 and Thr308 are phosphorylated at different stages of meiosis. In freshly isolated germinal vesicle (GV)-stage DOs Ser473 was already phosphorylated. After the onset of oocyte maturation the intensity of the Ser473-phosphorylation increased, however, declined sharply when DOs underwent germinal vesicle breakdown (GVBD) and remained at low levels in MI- and MII-stage. In contrast, phosphorylation of Thr308 increased by the time of GVBD and reached maximum at MI-stage. A peak of Akt activity was noticed around GVBD and activity of Akt declined at MI-stage. To assess the role of Akt during meiosis, porcine DOs were cultured in 50 muM of SH-6, a specific inhibitor of Akt. In SH-6-treated DOs GVBD was not inhibited, on the contrary a significant acceleration of meiosis resumption was observed. The dynamics of the Ser473-phosphorylation was not affected, however, phosphorylation of Thr308 was reduced, Akt activity was diminished at the time of GVBD and meiotic progression was arrested in early MI-stage. Moreover, the activity of the cyclin-dependent kinase 1 (Cdk1) and MAP kinase declined when SH-6-treated DOs underwent GVBD indicating that Akt activity is involved in the regulation of Cdk1 and MAP kinase. These results suggest that activity of Akt is not essential for induction of GVBD in porcine oocytes but plays a substantial role during progression of meiosis to MI/MII-stage. (Westfall SD et al 2000 ) reported a putative role of the phosphatidylinositol 3-kinase -Akt signaling pathway in the survival of granulosa cells. Treatment with IGF-I for 10 min stimulated PI 3-kinase and Akt protein kinase activity. IGF-I stimulated the phosphorylation and activation of Akt in a time- and concentration-dependent manner. The PI 3-kinase inhibitors wortmannin and LY294002 blocked IGF-I induced increases in Pi 3-kinase activity and phosphorylation of Akt. Additionally, IGF-I treatment prevented apoptosis, The survival response to IGF-I was blocked by treatment with either wortmannin or LY294002. Kalous J, et al reported that PKB/AKT is involved in resumption of meiosis in mouse oocytes. In fully-grown mouse oocytes, a decrease in cAMP concentration precedes and is linked to Cyclin-Dependent Kinase 1 (CDK1) activation. The molecular mechanism for this coupling, however, is not defined. Protein kinase B (PKB, also called AKT) is implicated in CDK1 activation in lower species. During resumption of meiosis in starfish oocytes PKB inhibitory phosphorylates MYT1, a negative regulator of CDK1. It can imply that PKB is also involved in CDK1 activation in mammalian oocytes. RESULTS: We monitored activation of PKB and CDK1 during maturation of mouse oocytes. PKB phosphorylation and activation preceded germinal vesicle breakdown (GVBD) in oocytes maturing either in vitro or in vivo. Activation was transient and PKB activity was markedly reduced when virtually all of the oocytes had undergone GVBD. PKB activation was independent of CDK1 activity, because although butyrolactone I prevented CDK1 activation and GVBD, PKB was nevertheless transiently phosphorylated and activated. LY-294002, an inhibitor of PI3K-PKB signaling, suppressed activation of PKB and CDK1 as well as resumption of meiosis. Okadaic acid (OA)-sensitive phosphatases are involved in PKB-activity regulation because OA induced PKB hyperphosphorylation. During resumption of meiosis PKB phosphorylated on S473 is associated with nuclear membrane and centrosome, whereas PKB phosphorylated on T308 is localized on centrosome only. CONCLUSIONS: Presented results indicate that PKB is involved in CDK1 activation and resumption of meiosis in mouse oocytes. The presence of phosphorylated PKB on centrosome at the time of GVBD suggests its important role for an initial CDK1 activation. Activation of Akt (protein kinase B) stimulates metaphase I to metaphase II transition in bovine oocytes Tomek W, et al . In somatic cells, the serine/threonine kinase Akt (or protein kinase B) was shown to contribute to processes linked to cellular growth, cell survival and cell cycle regulation. In contrast to these findings, the function of Akt during the meiosis of mammalian oocytes remains to be investigated. We analysed the phosphorylation pattern and the activity of Akt during meiotic maturation (transition from prophase I to metaphase II) of bovine oocytes. The oocytes were matured in vitro (IVM) for 0, 10 and 24 h to reach the germinal vesicle (GV), metaphase I (M I) and metaphase II (M II) stages respectively. The abundance and phosphorylation pattern of Akt was revealed by Western blotting using total Akt or phosphoso-Akt-specific antibodies. The activity of this particular kinase was determined by an in vitro kinase assay. Furthermore, functional properties were analysed by cultivating oocytes in the presence of the Akt inhibitor SH6. The results showed that the overall abundance of Akt did not change significantly during IVM. On the other hand, Akt became phosphorylated at Thr 308 and Ser 473, reaching its maximum at the M I phase. In the GV and M II stages, only low basal phosphorylation levels were observed on both sides. This phosphorylation profile corresponded strictly to the activity of the kinase. The cultivation of oocytes in the presence of the phosphatidylinositol analogue SH6 for 24 h showed that, with higher concentrations, up to 65% of the oocytes were arrested in the M I stage. This result indicated that Akt is involved in the M I/M II transition during the meiotic maturation of bovine oocytes. The physiological aspects of the Akt function will be discussed. 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. Protein kinase B (PKB/Akt) is required for the completion of meiosis in mouse oocytes. Hoshino Y et al. Akt, also known as protein kinase B, is implicated in many cellular processes. Akt is phosphorylated at two residues, Thr308 and Ser473. Thr308-phosphorylated Akt is present in pericentriolar materials, while localization of Ser473-phosphorylated Akt was similar to that of microtubules in metaphase oocytes. Spindles were shorter and aberrant in oocytes injected with Thr308- or Ser473-phosphorylated Akt antibodies. Specifically, Thr308- and Ser473-phosphorylated Akts function individually and are both necessary to assemble the metaphase II (MII) spindle. Moreover, the functions of Thr308- and Ser473-phosphorylated Akts differ in MII oocytes. Although oocytes exhibited second polar body (PB2) emission after the injection of a peptide for Thr308, the chromosomal alignment and microtubular organization were aberrant. In contrast, the injection of a peptide for Ser473 caused a failure of PB2 emission. These results suggest that Thr308- and Ser473-phosphorylated Akts are individually involved in fertilization to complete meiosis, including different roles (i.e., Ser473-phosphorylated Akts are involved in PB2 emission, whereas Thr308-phosphorylated Akts regulate the organization of microtubules). IGF1 induces up-regulation of steroidogenic and apoptotic regulatory genes via activation of phosphatidylinositol-dependent kinase/AKT in bovine granulosa cells. Mani AM et al. IGF1, a potent stimulator of cellular proliferation, differentiation and development, regulates granulosa cell steroidogenesis and apoptosis during follicular development. Depending upon species and stage of follicular growth, IGF1 acts on granulosa cell steroidogenesis either alone or together with FSH. We examined the mechanism of action of IGF1 in bovine granulosa cells in serum-free culture without insulin to determine its' potential role in the regulation of steroidogenic and apoptotic regulatory gene expression and to investigate the interaction of FSH with IGF1 on this mechanism. Bovine granulosa cells treated with IGF1 demonstrated a significant increase in 17beta-oestradiol production, cell number and in mRNA expression of CYP11A1, HSD3B1, CYP19A1, BAX, IGF1R and FSHR while FSH alone had no significant effects. IGF1 or FSH alone or both together had no effect on BCL2 expression. IGF1 with FSH resulted in a synergistic increase in granulosa cell number and in mRNA expression of CYP19A1 and IGF1R without altering 17beta-oestradiol production. IGF1 stimulated the PI3K but not the MAPK pathway in granulosa cells, as evidenced by increased phosphorylation of AKT but not ERK-1/2. Addition of the PI3K pathway inhibitor LY294002 (but not the MAPK pathway inhibitor PD98059) abrogated the increased expression of genes induced by IGF1. IGF1 therefore up-regulates the steroidogenic and apoptotic regulatory genes via activation of PI3K/AKT in bovine granulosa cells. The synergistic action of IGF1 with FSH is of likely key importance for the development of small antral follicles before selection; subsequently other factors such as LH may also become necessary for continued cell survival. Akt expression in mouse oocytes matured in vivo and in vitro. Cecconi S et al. To improve developmental competence of in vitro matured oocytes, culture medium can be supplemented with hypoxanthine (Hx) and FSH or epidermal growth factor (EGF) to trigger the activation of essential signalling pathways regulating meiotic resumption and progression. Since the serine/threonine kinase, Akt, contributes to the regulation of the meiotic cell cycle, this study analysed its expression level and localization at the meiotic spindle in oocytes matured in vivo or in vitro in the presence of Hx-FSH or Hx-EGF. Independently of culture conditions adopted, Akt mRNA concentration did not vary from germinal vesicle to metaphase I (MI), while at MII a significant decrease in Akt1 mRNA concentration was recorded in oocytes matured in vivo and in those stimulated by Hx-EGF (P < 0.05). Phoshorylated Akt protein content was similar in the different groups of MI oocytes, but it decreased at MII in oocytes matured either in vivo or in vitro with Hx-EGF. Ser-473-phosphorylated Akt was localized uniformly to the meiotic spindle in more than 90% of oocytes. These results indicate that, in mouse oocytes, Akt expression is differentially regulated during in vivo and in vitro maturation and suggest that EGF could be a positive modulator, even stronger than FSH, of oocyte meiotic maturation. Possible involvement of phosphatidylinositol 3-kinase in the maintenance of metaphase II attest in porcine oocytes matured in vitro. Ito J et al. ABSTRACT It has been reported that phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway plays a crucial role in the meiotic resumption and progression to the metaphase II (MII) stage of oocytes. However, the role of this pathway in meiotic arrest at the MII stage (cytostatic activity) is not well understood. In this study the effect of a PI3K inhibitor, LY294002, on the MAPK and p34(cdc2) kinase activities of matured porcine oocytes was examined. After maturation culture, both the MAPK and p34(cdc2) kinase activities in the oocytes were gradually decreased in a time-dependent manner. Although 25 micromol/L LY294002 did not affect either the MAPK or p34(cdc2) kinase activities, 50 micromol/L LY294002 suppressed the PKB phosphorylation and slightly decreased MAPK activity, but not the p34(cdc2) kinase activity. Therefore the effect of 10 micromol/L Ca(2+) ionophore which was reported as inducing a transient decrease of p34(cdc2) kinase but not MAPK activities, was also examined in LY294002-treated oocytes. By additional treatment with LY294002 after Ca(2+) ionophore, both the MAPK and p34(cdc2) kinase activities were decreased in a time-dependent manner, concomitantly with improvement of pronuclear formation. Therefore, we concluded that PI3K is involved in the maintenance of MAPK activity in matured porcine oocytes. | ||||
| Expression regulated by | FSH, LH, Growth Factors/ cytokines | ||||
| Comment | Zeleznik AJ, et al reported that Protein kinase B is obligatory for follicle-stimulating hormone-induced granulosa cell differentiation. Taylor CC 2000 reported that platelet-derived growth factor activates porcine thecal cell phosphatidylinositol-3-kinase-Akt/PKB and ras-extracellular signal-regulated kinase-1/2 kinase signaling pathways via the platelet-derived growth factor-beta receptor. They demonstrate the expression of immunoreactive PDGF-Rbeta, but not PDGF-Ralpha, in the thecal and stromal compartments of intact porcine ovaries as well as in cultured porcine thecal cells. Treatment of porcine thecal cells in vitro with PDGF resulted in rapid and sustained tyrosine phosphorylation of PDGF-Rbeta, activation of Src tyrosine kinase and phosphatidylinositol-3-kinase (PI3-kinase), and serine 473 phosphorylation of Akt/protein kinase B. In addition, PDGF stimulated an increase in GTP-Ras (activated Ras) and extracellular signal-regulated kinase (ERK) phosphorylation. Both forms of PDGF, AB and BB, stimulated thecal cell growth approximately 3- to 4-fold over controls and inhibited LH-stimulated progesterone and androstenedione secretion. Blockade of PI3-kinase activation with wortmannin had no effect on PDGF-stimulated thecal cell growth or PDGF inhibition ofLH-stimulated steroid secretion, indicating that PI3-kinase activation is not necessary for PDGF-stimulated thecal cell growth or inhibition of LH-stimulated steroidogenesis. Gonzalez-Robayna IJ, et al reported that Follicle-Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk) in granulosa cells. In these studies three kinases were investigated to determine their relationship to FSH, cAMP, and A kinase signaling: protein kinase B (PKB/Akt), serum and glucocorticoid-induced kinase (Sgk), and p38 mitogen-activated protein kinase (p38MAPK). The phosphorylation (activation) of these kinases was analyzed by using selective agonists/inhibitors: forskolin/H89 for cAMP-dependent protein kinase (A kinase), insulin-like growth factor I (IGF-I)/LY294002 and wortmannin for phosphatidylinositol-dependent kinase (PI3-K), and phorbol myristate (PMA)/GF109203X for diacylglycerol and Ca++-dependent kinases (C kinases). An inhibitor (PD98059) of MEK1, which regulates extracellular regulated kinases (ERKs), and SB203580, which inhibits p38MAPK, were also used. FSH, forskolin, and 8-bromo-cAMP stimulate phosphorylation of PKB by mechanisms involving PI3-K (LY294002/wortmannin sensitive) not A kinase (H89 insensitive), a pattern of response mimicking that of IGF-I. The authors propose that cAMP activation of A kinase is obligatory for transcription of Sgk in granulosa cells whereas cAMP (IGF-I-like)-mediated phosphorylation (activation) of PKB and Sgk (via PI3-K), as well as p38MAPK, involves other cellular events. Follicle Stimulating Hormone Inhibits AMPK Activation and Promotes Cell Proliferation of Primary Granulosa Cells in Culture Through an Akt Dependent Pathway. Kayampilly PP et al. FSH, acting through multiple signaling pathways regulates the proliferation and growth of granulosa cells which are critical for ovulation. The present study investigated whether AMP Kinase, which controls the energy balance of the cell, plays a role in FSH-mediated increase in granulosa cell proliferation. Cells isolated from immature rat ovaries were grown in serum free, phenol red free DMEM-F12 and were treated with FSH (50 ng/mL) for 0, 5, and 15 min. Western blot analysis showed a significant reduction in AMPK activation as observed by a reduction of phosphorylation at thr 172 in response to FSH treatment at all time points tested. FSH also reduced AMPK phosphorylation in a dose dependent manner with maximum inhibition at 100 ng/ml. The chemical activator of AMPK (AICAR, 0.5mM) increased the cell cycle inhibitor p27 kip expression significantly, whereas the AMPK inhibitor (compound C, 20microM) and FSH reduced p27kip expression significantly compared to control. FSH treatment resulted in an increase in the phosphorylation of AMPK at ser 485/491 while reducing thr 172 phosphorylation. Inhibition of Akt phosphorylation using Akt inhibitor VIII reversed the inhibitory effect of FSH on thr 172 phosphorylation of AMPK whereas ERK inhibitor U0126 had no effect. These results show that FSH, through an Akt dependent pathway, phosphorylates AMPK at ser 481/495 and inhibits its activation by reducing thr 172 phosphorylation. AMPK activation by AICAR treatment resulted in a reduction of cell cycle regulatory protein cyclin D2 mRNA expression whereas FSH increased the expression by two fold. These results suggest that FSH promotes granulosa cell proliferation by increasing cyclin D2 mRNA expression and by reducing p27 kip expression by inhibiting AMPK activation through an Akt-dependent pathway. Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells. Fukuda S et al. ABSTRACT: BACKGROUND: Theca cells play an important role in controlling ovarian steroidogenesis by providing aromatizable androgens for granulosa cell estrogen biosynthesis. Although it is well established that the steroidogenic activity of theca cells is mainly regulated by LH, the intracellular signal transduction mechanisms that regulate thecal proliferation and/or steroidogenesis remain obscure. In this study, we examined whether and how LH controls the PI3K/Akt signaling pathway and androgen production in bovine theca cells. We also explored whether this LH-induced PI3K/Akt activation is modulated with other signaling pathways (i.e. PKA and MAPK). METHODS: Ovarian theca cells were isolated from bovine small antral follicles and were incubated with LH for various durations. Phospho-Akt and total-Akt content in the cultured theca cells were examined using Western blotting. Androstenedione levels in the spent media were determined using EIA. Semi-quantitative RT-PCR analyses were conducted to analyze the mRNA levels of CYP17A1 and StAR in the theca cells. To examine whether Akt activity is involved in theca cell androgen production, the PI3K inhibitors wortmannin and LY294002 were also added to the cells. RESULTS: Akt is constitutively expressed, but is gradually phosphorylated in cultured bovine theca cells through exposure to LH. LH significantly increased androstenedione production in bovine theca cells, whereas addition of the wortmannin and LY294002 significantly decreased LH-induced androstenedione production. LH significantly increased CYP17A1 mRNA level in theca cells, whereas addition of LY294002 significantly decreased LH-induced CYP17A1 expression. Neither LH nor PI3K inhibitors alter the mRNA levels of StAR in theca cells. Although H89 (a selective inhibitor of PKA) does not affect LH-mediated changes in Akt, U0126 (a potent MEK inhibitor) suppressed LH-induced Akt phosphorylation, CYP17A1 expression, and androgen production in theca cells. CONCLUSION: These results indicate that LH stimulates CYP17 mRNA expression and androgen production in theca cells via activation of the PI3K/Akt pathway. The LH-induced Akt phosphorylation and androgen production are modulated by the MAPK signaling in bovine theca cells. | ||||
| Ovarian localization | Oocyte, Granulosa, Theca, Surface epithelium | ||||
| Comment | Bellacosa A et al reported molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas . No AKT2 alteration was detected in 24 benign or borderline tumors. Northern-blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness. Insulin Signaling in Mammalian Oocytes. Acevedo N et al. Continual exposure of follicles/oocytes to elevated insulin compromises embryonic developmental competence, yet cellular mechanisms are unknown. Objectives of present studies were to determine if mouse oocytes have insulin receptors, a functional insulin signaling cascade, and whether insulin exposure during oocyte growth or maturation influences meiotic progression and chromatin remodeling. Immunoblot and immunocytochemical analyses of germinal vesicle-intact (GVI) oocytes demonstrated presence of insulin receptor-beta. Insulin receptor expression was increased in oocytes following gonadotropin stimulation, and remained elevated throughout meiotic maturation. Fully-grown GVI oocytes contained 3-phosphoinositide dependent protein kinase-1 (PDPK1), thymoma viral proto-oncogene 1 (AKT1) and glycogen synthase kinase 3 (GSK3). In vitro maturation of GVI oocytes in 5 microg/ml insulin had no influence on meiotic progression or incidence of normal MII chromosome condensation. Treatment of oocytes during maturation had no effect on GSK3A/B protein expression or phosphorylation on S21/9. However, culture of pre-antral follicles for 10 days with 5 microg/ml insulin increased phosphorylation of oocyte GSK3B, indicating GSK3 inactivation. Rate of development to MI was similar between oocytes obtained from insulin treated follicles and controls, yet incidence of abnormal MI chromatin condensation was significantly higher in oocytes obtained from follicles cultured with insulin compared to no insulin. These results demonstrate that oocytes contain a functional insulin signaling pathway and that insulin exposure during oocyte growth results in chromatin remodeling aberrations. These findings begin to elucidate mechanisms by which chronic elevated insulin influences oocyte meiosis, chromatin remodeling, and embryonic developmental competence. | ||||
| Follicle stages | Antral, Preovulatory | ||||
| Comment | The role of Akt signalling in the mammalian ovary. Cecconi S et al. The serine/threonine protein kinase Akt is involved in many cellular processes including cell growth, survival, proliferation and metabolism. Akt activity is modulated downstream of phosphatidylinositol-3-kinase (PI3K) in response to different extracellular stimuli. In the mammalian ovary, Akt collaborates with other kinases in the regulation of coordinate follicle and oocyte development. Akt determines the pool of primordial follicles and the transition from quiescent to growing phase. In addition, the kinase modulates granulosa cell apoptosis throughout folliculogenesis. In oocytes Akt participates in the control of meiosis resumption and, at metaphase II stage, regulates polar body emission and spindle organization. Its inhibition negatively affects preimplantation embryo development. As a consequence of such a central role, Akt dysregulation is associated with several human diseases including infertility and ovarian cancer. | ||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
4 mutations
Species: mouse
Species: human
Species: mouse
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | July 10, 2000, midnight | by: |
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| last update: | Feb. 27, 2020, 12:55 p.m. | by: | hsueh email: |
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