Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At the late blastocyst stage, the epithelial trophectoderm cells of the mammalian embryo undergo a phenotypic change that allows them to invade into the uterine stroma and make contact with the maternal circulation. This step can be regulated in vitro by the availability of amino acids. Embryos cultured in defined medium lacking amino acids cannot form trophoblast cell outgrowths on fibronectin, an in vitro model of implantation, but remain viable for up to 3 days in culture and will form outgrowths when transferred into complete medium. The amino acid requirement is a developmentally regulated permissive event that occurs during a 4- to 8-h period at the early blastocyst stage. Amino acids affect spreading competence specifically by regulating the onset of protrusive activity and not the onset of integrin activation. Rapamycin, a specific inhibitor of the kinase mTOR/FRAP/RAFT1, blocks amino acid stimulation of embryo outgrowth, demonstrating that mTOR is required for the initiation of trophectoderm protrusive activity. Inhibition of global protein translation with cycloheximide also inhibits amino acid-dependent signals, suggesting that mTOR regulates the translation of proteins required for trophoblast differentiation. Our data suggest that mTOR activity has a developmental regulatory function in trophectoderm differentiation that may serve to coordinate embryo and uterus at the time of implantation.
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PMID:Exogenous amino acids regulate trophectoderm differentiation in the mouse blastocyst through an mTOR-dependent pathway. 1178 55

This study examined the role of osteopontin (OPN), a phosphorylated secreted glycoprotein, in the promotion of trophoblastic cell migration, an early event in the embryo implantation process. Three human choriocarcinoma cell lines, namely JAR, BeWo, and JEG-3, were treated with variants of OPN differing in the extent of phosphorylation following sequential dephosphorylation with tartrate-resistant acid phosphatase (TRAP), and their migratory response was measured. The highly phosphorylated human milk form of OPN (OPN-1) strongly triggered migration in all three cell lines, whereas the less phosphorylated variants, OPN-2a and OPN-2b, failed to stimulate migration. JAR cell migration in response to OPN-1 was accompanied by a rapid rearrangement of actin filaments to the cellular membrane. Using broad spectrum protein kinase profiling, we identified p70 S6 kinase as a major signal transduction pathway activated by OPN-1 during the migratory response in JAR cells. Activation was blocked completely by rapamycin and LY294002, thus demonstrating that OPN-1-stimulated migration occurs through mTOR and PI3K pathways, respectively. Conversely, PD98059 did not affect the activation of p70 S6 kinase by OPN-1, therefore, this response does not involve the Ras/ MAPK signaling cascade. Together, these data show that the highly phosphorylated human OPN-1 can stimulate trophoblastic cell migration and provides evidence for the involvement of the PI3K/mTOR/p70 S6 kinase pathway in the JAR cells response. Because both OPN and TRAP are expressed in the uterus during early pregnancy, it is conceivable that extracellular phosphatases such as TRAP may modify OPN charge state and thus modulate cell migration.
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PMID:Phosphorylated osteopontin promotes migration of human choriocarcinoma cells via a p70 S6 kinase-dependent pathway. 1569 79

Amino acid transport system B(0,+) was first characterized in detail in mouse blastocysts over two decades ago. Since then, this system has been shown to be involved in a wide array of developmental processes from blastocyst implantation in the uterus to adult obesity. Leucine uptake through system B(0,+) in blastocysts triggers mammalian target of rapamycin (mTOR) signalling. This signalling pathway selectively regulates development of trophoblast motility and the onset of the penetration stage of blastocyst implantation about 20 h later. Meanwhile, system B(0,+) becomes inactive in blastocysts a few hours before implantation in vivo. System B(0,+) can, however, be activated in preimplantation blastocysts by physical stimuli. The onset of trophoblast motility should provide the physiological physical stimulus activating system B(0,+) in blastocysts in vivo. Activation of system B(0,+) when trophoblast cells begin to penetrate the uterine epithelium would cause it to accumulate its preferred substrates, which include tryptophan, from uterine secretions. A low tryptophan concentration in external secretions next to trophoblast cells inhibits T-cell proliferation and rejection of the conceptus. Suboptimal system B(0,+) regulation of these developmental processes likely influences placentation and subsequent embryo nutrition, birth weight and risk of developing metabolic syndrome and obesity.
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PMID:System B0,+ amino acid transport regulates the penetration stage of blastocyst implantation with possible long-term developmental consequences through adulthood. 1625 Dec 51

Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter; however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.
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PMID:Comparative integromics on Angiopoietin family members. 1668 28

In this review, we describe a new model to explain the regulation of myometrial function during pregnancy and labour. We propose that the myometrium undergoes dramatic changes in phenotype from early pregnancy until the onset of labour, characterized by an early proliferative phase, an intermediate phase of cellular hypertrophy and matrix elaboration, a third phase in which the cells assume a contractile phenotype and the final phase in which cells become highly active and committed to labour. The last phase of myometrial differentiation is postpartum uterine involution, completing the reproductive cycle following pregnancy and labour by returning the uterus to its non-pregnant receptive state. We further propose that phenotypic modulation of the uterine myocytes is the result of integration of endocrine signals and mechanical stimulation of the uterus by the growing fetus. Our previous studies have shown that these signals are important in regulating the onset of labour and we now have indications that they regulate earlier myometrial smooth muscle differentiation. We show that the high rate of myometrial cell proliferation in early pregnancy which reflects important aspects of many smooth muscle populations during development. The proliferative phenotype was associated with dramatic changes in the expression of IGF family proteins and coincided with an up-regulation of the anti-apoptotic pathway. Preliminary evidence suggests that myometrial hyperplasia was controlled by the PI3K-Akt-mTOR signaling pathway. The modulation of the mTOR pathway by rapamycin blocked the proliferative activity of the uterine myocytes. The growth and remodeling of the myometrium during pregnancy was associated with increased synthesis of extra cellular matrix (ECM) proteins and their corresponding integrin receptors. Our results show a decrease in expression of fibrillar collagens and a coordinated temporal increase in expression of components of the basement membrane near term associated with decreased progesterone levels and increased mechanical tension. The phenotypic modulation of uterine smooth muscle cells during pregnancy culminates at term when a myometrium-specific conversion commits these cells to the labour phenotype, characterized by increased excitability, spontaneous activity, responsiveness to agonists and effective coupling of the myocytes. The reinforcement of the ECM-integrin interaction contributes to myometrial hypertrophy and remodeling during late pregnancy and facilitates force transduction during the contractions of labour by anchoring hypertrophied SMCs to the uterine ECM. In addition, we suggest that myometrial cells play an important role in the generation and regulation of uterine inflammation, which is a characteristic feature of parturition. We provide here substantial evidence that myometrial cells can actively participate in the inflammatory process in the uterus by the release of the pro-inflammatory chemokine MCP-1. The increased production of MCP-1 in the term myometrium was associated with uterine occupancy and regulated by progesterone, suggesting that mechanical and endocrine signals integrate to regulate the expression of the chemokine and the induction of labour. A better understanding of the mechanisms regulating myometrial differentiation during pregnancy might inform the development of new therapeutic strategies for the management of preterm labour, which remains a leading cause of neonatal morbidity and mortality. Our data are obtained mostly from the rat, but we believe that they are generally applicable across species.
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PMID:Integration of endocrine and mechanical signals in the regulation of myometrial functions during pregnancy and labour. 1929 64

FRAP1 (FK506-binding protein 12-rapamycin complex-associated protein 1), a component of the nutrient-sensing cell signaling pathway, is critical for cell growth and metabolism. The present study determined expression of FRAP1 and associated members of the mTORC1 and mTORC2 cell signaling pathways in uteri of cyclic and pregnant ewes and conceptuses, as well as effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on their expression. The mRNAs for FRAP1, LST8, MAPKAP1, RAPTOR, RICTOR, TSC1, TSC2, RHEB, and EIF4EBP1 were localized to luminal, superficial glandular, and glandular epithelia and stromal cells of uteri from cyclic and pregnant ewes, as well as trophectoderm and endoderm of conceptuses between Days 13 and 18 of pregnancy. The abundance of FRAP1, RAPTOR, RICTOR, TSC1, and TSC2 mRNAs in endometria was unaffected by pregnancy status or by day of the estrous cycle or pregnancy; however, levels of LST8, MAPKAP1, RHEB, and EIF4EBP1 mRNA increased in endometria during early pregnancy. In ovariectomized ewes, P4 and IFNT stimulated expression of RHEB and EIF4EBP1 in uterine endometria. Total endometrial FRAP1 protein and phosphorylated FRAP1 protein levels were affected by pregnancy status and by day after onset of estrus, and phosphorylated FRAP1 protein was detected in nuclei of uterine epithelia and conceptuses. In endometria of pregnant ewes, increases in abundance of mRNAs for RICTOR, RHEB, and EIF4EBP1, as well as RHEB protein, correlated with rapid conceptus growth and development during the peri-implantation period. These results suggest that the FRAP1 cell signaling pathway mediates interactions between the maternal uterus and peri-implantation conceptuses and that P4 and IFNT affect this pathway by regulating expression of RHEB and EIF4EBP1.
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PMID:Select nutrients in the ovine uterine lumen. VI. Expression of FK506-binding protein 12-rapamycin complex-associated protein 1 (FRAP1) and regulators and effectors of mTORC1 and mTORC2 complexes in ovine uteri and conceptuses. 1929 12

Mammalian target of rapamycin (MTOR) is a protein kinase that plays a central role in cell growth and proliferation. It is a part of the signaling network transmitting growth factor signaling to translational control. Previous studies have shown that MTOR is involved in embryo implantation, but its expression in the uterus and its role in implantation are unclear. Here, we have investigated the expression and role of MTOR in mouse uterus during early pregnancy. RT-FQ PCR showed that the mRNA levels of Mtor in endometria of pregnant mice were higher than those of nonpregnant mice. The mRNA levels in the pregnant mice gradually increased from D3 of pregnancy, reached maximum on D5, and then declined afterward. In situ hybridization and immunohistochemical analysis showed that the mRNA and protein of MTOR were mainly located in stromal cells. The levels of the expressed MTOR protein correlate with those of mRNA. The number of implantation sites was greatly decreased by the intrauterine injection with rapamycin in the early morning of D4 of the pregnancy. These findings suggest that MTOR may play an important role in embryo implantation in mice.
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PMID:The role of MTOR in mouse uterus during embryo implantation. 1944 11

The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.
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PMID:Mammalian target of rapamycin is activated in association with myometrial proliferation during pregnancy. 1958 61

Endometrial cancer--the most common malignancy of the female reproductive tract--arises from the specialized epithelial cells that line the inner surface of the uterus. Although significant advances have been made in our understanding of this disease in recent years, one significant limitation has been the lack of a diverse genetic toolkit for the generation of mouse models. We identified a novel endometrial-specific gene, Sprr2f, and developed a Sprr2f-Cre transgene for conditional gene targeting within endometrial epithelium. We then used this tool to generate a completely penetrant Lkb1 (also known as Stk11)-based mouse model of invasive endometrial cancer. Strikingly, female mice with homozygous endometrial Lkb1 inactivation did not harbor discrete endometrial neoplasms, but instead underwent diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, suggesting that Lkb1 inactivation was sufficient to promote the development of invasive endometrial cancer. Mice with heterozygous endometrial Lkb1 inactivation only rarely developed tumors, which were focal and arose with much longer latency, arguing against the idea--suggested by some prior studies--that Lkb1 is a haploinsufficient tumor suppressor. Lastly, the finding that endometrial cancer cell lines were especially sensitive to the mTOR (mammalian target of rapamycin) inhibitor rapamycin prompted us to test its efficacy against Lkb1-driven endometrial cancers. Rapamycin monotherapy not only greatly slowed disease progression, but also led to striking regression of pre-existing tumors. These studies demonstrate that Lkb1 is a uniquely potent endometrial tumor suppressor, but also suggest that the clinical responses of some types of invasive cancers to mTOR inhibitors may be linked to Lkb1 status.
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PMID:Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. 2014 30

Attachment and migration of trophectoderm (Tr) cells, hallmarks of blastocyst implantation in mammals, are unique uterine events. Secreted phosphoprotein 1 (SPP1) in the uterus binds integrins on conceptus Tr and uterine luminal epithelium (LE), affecting cell-cell and cell-matrix interactions. The signal transduction pathways activated by SPP1 and integrins in conceptuses have not been elucidated. Results of this study demonstrate that SPP1 binds alphavbeta3 and alpha5beta1 integrins to induce focal adhesion assembly, a prerequisite for adhesion and migration of Tr, through activation of: 1) P70S6K via crosstalk between FRAP1/mTOR and MAPK pathways; 2) mTOR, PI3K, MAPK3/MAPK1 (Erk1/2) and MAPK14 (p38) signaling to stimulate Tr cell migration; and 3) focal adhesion assembly and myosin II motor activity to induce migration of Tr cells. These cell signaling pathways, acting in concert, mediate adhesion, migration and cytoskeletal remodeling of Tr cells essential for expansion and elongation of conceptuses and attachment to uterine LE for implantation.
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PMID:Secreted phosphoprotein 1 binds integrins to initiate multiple cell signaling pathways, including FRAP1/mTOR, to support attachment and force-generated migration of trophectoderm cells. 2038 32


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