Role of Akt and mammalian target of rapamycin signalling in insulin-like growth factor 1-mediated cell proliferation in porcine Sertoli cells
Chinju Johnson
A , John Kastelic A and Jacob Thundathil A B
+ Author Affiliations
- Author Affiliations
A Department of Production Animal Health, Faculty of Veterinary Medicine, 3330 Hospital Drive NW, University of Calgary, Calgary, AB T2N 4N1, Canada.
B Corresponding author. Email: jthundat@ucalgary.ca
Reproduction, Fertility and Development 32(10) 929-940 https://doi.org/10.1071/RD19460
Submitted: 17 December 2019 Accepted: 4 May 2020 Published: 15 June 2020
Abstract
The critical role of insulin-like growth factor (IGF) 1 in promoting Sertoli cell proliferation in vivo and in vitro has been established, but its downstream signalling mechanisms remain unknown. In addition to mitogenic effects, a role for IGF1 in mediating cholesterol biosynthesis within testes has been implied. The aims of this study were to investigate the roles of: (1) phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signalling in IGF1-mediated Sertoli cell proliferation; and (2) IGF1 in mediating cholesterol biosynthesis in Sertoli cells. Primary cultures of Sertoli cells were prepared from 1-week-old porcine testes. On Day 3 of culture, Sertoli cells were treated with 300 ng mL−1 IGF1, alone or in combination with inhibitors of IGF1 receptor (2 μM picropodophyllotoxin), Akt (1 μM wortmannin) or mTOR (200 nM rapamycin). Cells were cultured for 30 min and phosphorylation levels of Akt, mTOR and p70 ribosomal protein S6 kinase (p70S6K) were determined by immunoblotting. Cell proliferation and quantitative polymerase chain reaction assays were conducted using cells cultured for 24 h. IGF1 increased phosphorylation of Akt, mTOR and p70S6K and cell proliferation, and these effects were inhibited by inhibitors of IGF1R, Akt and mTOR. Furthermore, IGF1 upregulated the expression of cholesterol biosynthetic genes (3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS1) and cytochrome P450, family 5, subfamily A, polypeptide 1 (CYP5A1)), but not sterol regulatory element-binding transcription factor 1 (SREBF1). Increased phosphorylation of p70S6K, a major downstream target of mTOR, and upregulated expression of genes involved in cholesterol biosynthesis are indicative of the key role played by IGF1 in regulating the synthesis of cholesterol, the precursor for steroid hormones.
Additional keyword: cholesterol biosynthesis.
References
Alessi, D. R., Andjelkovic, M., Caudwell, B., Cron, P., Morrice, N., Cohen, P., and Hemmings, B. A. (1996). Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541–6551.| Mechanism of activation of protein kinase B by insulin and IGF-1.Crossref | GoogleScholarGoogle Scholar | 8978681PubMed |
Arcaro, A., and Wymann, M. P. (1993). Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297–301.
| Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses.Crossref | GoogleScholarGoogle Scholar | 8257416PubMed |
Averous, J., Fonseca, B. D., and Proud, C. G. (2008). Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27, 1106–1113.
| Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1.Crossref | GoogleScholarGoogle Scholar | 17724476PubMed |
Avruch, J. (1998). Insulin signal transduction through protein kinase cascades. Mol. Cell. Biochem. 182, 31–48.
| Insulin signal transduction through protein kinase cascades.Crossref | GoogleScholarGoogle Scholar | 9609112PubMed |
Bhasker, C. R., and Friedmann, T. (2008). Insulin-like growth factor-1 coordinately induces the expression of fatty acid and cholesterol biosynthetic genes in murine C2C12 myoblasts. BMC Genomics 9, 535.
| Insulin-like growth factor-1 coordinately induces the expression of fatty acid and cholesterol biosynthetic genes in murine C2C12 myoblasts.Crossref | GoogleScholarGoogle Scholar | 19014463PubMed |
Brown, M. S., and Goldstein, J. L. (1974). Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. J. Biol. Chem. 249, 7306–7314.
| 4436312PubMed |
Buck, E., Gokhale, P. C., Koujak, S., Brown, E., Eyzaguirre, A., Tao, N., Rosenfeld-Franklin, M., Lerner, L., Chiu, M. I., Wild, R., Epstein, D., Pachter, J. A., and Miglarese, M. R. (2010). Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol. Cancer Ther. 9, 2652–2664.
| Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer.Crossref | GoogleScholarGoogle Scholar | 20924128PubMed |
Buonomo, F. C., and Klindt, J. (1993). Ontogeny of growth hormone (GH), insulin-like growth factors (IGF-I and IGF-II) and IGF binding protein-2 (IGFBP-2) in genetically lean and obese swine. Domest. Anim. Endocrinol. 10, 257–265.
| Ontogeny of growth hormone (GH), insulin-like growth factors (IGF-I and IGF-II) and IGF binding protein-2 (IGFBP-2) in genetically lean and obese swine.Crossref | GoogleScholarGoogle Scholar | 7504606PubMed |
Cannarella, R., Condorelli, R. A., La Vignera, S., and Calogero, A. E. (2018). Effects of the insulin-like growth factor system on testicular differentiation and function: a review of the literature. Andrology 6, 3–9.
| Effects of the insulin-like growth factor system on testicular differentiation and function: a review of the literature.Crossref | GoogleScholarGoogle Scholar | 29195026PubMed |
Cannarella, R., Arato, I., Condorelli, R. A., Luca, G., Barbagallo, F., Alamo, A., Bellucci, C., Lilli, C., La Vignera, S., Calafiore, R.,, Mancuso, F., and Calogero, A. E. (2019a). The IGF1 receptor is involved in follicle-stimulating hormone signaling in porcine neonatal Sertoli cells. J. Clin. Med. 8, 577.
| The IGF1 receptor is involved in follicle-stimulating hormone signaling in porcine neonatal Sertoli cells.Crossref | GoogleScholarGoogle Scholar |
Cannarella, R., Mancuso, F., Condorelli, R. A., Arato, I., Mongioì, L. M., Giacone, F., Lilli, C., Bellucci, C., La Vignera, S., Calafiore, R., Luca, G., and Calogero, A. E. (2019b). Effects of GH and IGF1 on basal and FSH-modulated porcine sertoli cells in-vitro. J. Clin. Med. 8, 811.
| Effects of GH and IGF1 on basal and FSH-modulated porcine sertoli cells in-vitro.Crossref | GoogleScholarGoogle Scholar |
Chatelain, P. G., Naville, D., and Saez, J. M. (1987). Somatomedin-C/insulin-like growth factor I-like material secreted by porcine Sertoli cells in vitro: characterization and regulation. Biochem. Biophys. Res. Commun. 146, 1009–1017.
| Somatomedin-C/insulin-like growth factor I-like material secreted by porcine Sertoli cells in vitro: characterization and regulation.Crossref | GoogleScholarGoogle Scholar | 3619911PubMed |
Chen, H. W., Leonard, D. A., Fischer, R. T., and Trzaskos, J. M. (1988). A mammalian mutant cell lacking detectable lanosterol 14 alpha-methyl demethylase activity. J. Biol. Chem. 263, 1248–1254.
| 3335544PubMed |
Curtis, S. K., and Amann, R. P. (1981). Testicular development and establishment of spermatogenesis in Holstein bulls. J. Anim. Sci. 53, 1645–1657.
| Testicular development and establishment of spermatogenesis in Holstein bulls.Crossref | GoogleScholarGoogle Scholar | 7341622PubMed |
Dance, A., Thundathil, J., Wilde, R., Blondin, P., and Kastelic, J. (2015). Enhanced early-life nutrition promotes hormone production and reproductive development in Holstein bulls. J. Dairy Sci. 98, 987–998.
| Enhanced early-life nutrition promotes hormone production and reproductive development in Holstein bulls.Crossref | GoogleScholarGoogle Scholar | 25497791PubMed |
Dance, A., Thundathil, J., Blondin, P., and Kastelic, J. (2016). Enhanced early-life nutrition of Holstein bulls increases sperm production potential without decreasing postpubertal semen quality. Theriogenology 86, 687–694.e2.
| Enhanced early-life nutrition of Holstein bulls increases sperm production potential without decreasing postpubertal semen quality.Crossref | GoogleScholarGoogle Scholar | 27114168PubMed |
Dance, A., Kastelic, J., and Thundathil, J. (2017). A combination of insulin-like growth factor I (IGF-I) and FSH promotes proliferation of prepubertal bovine Sertoli cells isolated and cultured in vitro. Reprod. Fertil. Dev. 29, 1635–1641.
| A combination of insulin-like growth factor I (IGF-I) and FSH promotes proliferation of prepubertal bovine Sertoli cells isolated and cultured in vitro.Crossref | GoogleScholarGoogle Scholar | 27700982PubMed |
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., Vander Heiden, M. G., MacKeigan, J. P., Finan, P. M., Clish, C. B., Murphy, L. O., and Manning, B. D. (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183.
| Activation of a metabolic gene regulatory network downstream of mTOR complex 1.Crossref | GoogleScholarGoogle Scholar | 20670887PubMed |
Goldstein, J. L., and Brown, M. S. (1990). Regulation of the mevalonate pathway. Nature 343, 425–430.
| Regulation of the mevalonate pathway.Crossref | GoogleScholarGoogle Scholar | 1967820PubMed |
Guertin, D. A., and Sabatini, D. M. (2007). Defining the role of mTOR in cancer. Cancer Cell 12, 9–22.
| Defining the role of mTOR in cancer.Crossref | GoogleScholarGoogle Scholar | 17613433PubMed |
Hansson, V., Weddington, S. C., French, F. S., McLean, W., Smith, A., Nayfeh, S. N., Ritzén, E. M., and Hagenäs, L. (1976). Secretion and role of androgen-binding proteins in the testis and epididymis. J. Reprod. Fertil. Suppl. 24, 17–33.
Himpe, E., and Kooijman, R. (2009). Insulin-like growth factor-I receptor signal transduction and the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Biofactors 35, 76–81.
| Insulin-like growth factor-I receptor signal transduction and the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway.Crossref | GoogleScholarGoogle Scholar | 19319849PubMed |
Hinchy, E. C., Gruszczyk, A. V., Willows, R., Navaratnam, N., Hall, A. R., Bates, G., Bright, T. P., Krieg, T., Carling, D., and Murphy, M. P. (2018). Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J. Biol. Chem. 293, 17208–17217.
| Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly.Crossref | GoogleScholarGoogle Scholar | 30232152PubMed |
Horton, J. D., Shah, N. A., Warrington, J. A., Anderson, N. N., Park, S. W., Brown, M. S., and Goldstein, J. L. (2003). Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl Acad. Sci. USA 100, 12027–12032.
| Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.Crossref | GoogleScholarGoogle Scholar | 14512514PubMed |
Johnson, C., Dance, A., Kovalchuk, I., Kastelic, J., and Thundathil, J. (2019). Enhanced early-life nutrition upregulates cholesterol biosynthetic gene expression and Sertoli cell maturation in testes of pre-pubertal Holstein bulls. Sci. Rep. 9, 6448.
| Enhanced early-life nutrition upregulates cholesterol biosynthetic gene expression and Sertoli cell maturation in testes of pre-pubertal Holstein bulls.Crossref | GoogleScholarGoogle Scholar | 31015481PubMed |
Kahn, C. R., and White, M. F. (1988). The insulin receptor and the molecular mechanism of insulin action. J. Clin. Invest. 82, 1151–1156.
| The insulin receptor and the molecular mechanism of insulin action.Crossref | GoogleScholarGoogle Scholar | 3049671PubMed |
Khan, S. A., Ndjountche, L., Pratchard, L., Spicer, L. J., and Davis, J. S. (2002). Follicle-stimulating hormone amplifies insulin-like growth factor i-mediated activation of AKT/protein kinase B signaling in immature rat Sertoli cells. Endocrinology 143, 2259–2267.
| Follicle-stimulating hormone amplifies insulin-like growth factor i-mediated activation of AKT/protein kinase B signaling in immature rat Sertoli cells.Crossref | GoogleScholarGoogle Scholar | 12021190PubMed |
Kim, J. E., and Chen, J. (2004). Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53, 2748–2756.
| Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis.Crossref | GoogleScholarGoogle Scholar | 15504954PubMed |
Laplante, M., and Sabatini, D. M. (2009). mTOR signaling at a glance. J. Cell Sci. 122, 3589–3594.
| mTOR signaling at a glance.Crossref | GoogleScholarGoogle Scholar | 19812304PubMed |
Lee, Y. K., Park, S. Y., Kim, Y. M., Kim, D. C., Lee, W. S., Surh, Y. J., and Park, O. J. (2010). Suppression of mTOR via Akt-dependent and -independent mechanisms in selenium-treated colon cancer cells: involvement of AMPKα. Carcinogenesis 31, 1092–1099.
| Suppression of mTOR via Akt-dependent and -independent mechanisms in selenium-treated colon cancer cells: involvement of AMPKα.Crossref | GoogleScholarGoogle Scholar | 20164123PubMed |
Li, S. F., Tong, H. L., Liu, C. C., and Yan, Y. Q. (2011). Effects of IGF-I on the proliferation of testis Sertoli cells in mouse. Adv. Mat. Res. 287–290, 112–115.
| Effects of IGF-I on the proliferation of testis Sertoli cells in mouse.Crossref | GoogleScholarGoogle Scholar |
Lunstra, D. D., Ford, J. J., and Echternkamp, S. E. (1978). Puberty in beef bulls: hormone concentrations, growth, testicular development, sperm production and sexual aggressiveness in bulls of different breeds. J. Anim. Sci. 46, 1054–1062.
| Puberty in beef bulls: hormone concentrations, growth, testicular development, sperm production and sexual aggressiveness in bulls of different breeds.Crossref | GoogleScholarGoogle Scholar | 566747PubMed |
Memmott, R. M., and Dennis, P. A. (2009). Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell. Signal. 21, 656–664.
| Akt-dependent and -independent mechanisms of mTOR regulation in cancer.Crossref | GoogleScholarGoogle Scholar | 19166931PubMed |
Mita, M., Borland, K., Price, J. M., and Hall, P. F. (1985). The influence of insulin and insulin-like growth factor-I on hexose transport by Sertoli cells. Endocrinology 116, 987–992.
| The influence of insulin and insulin-like growth factor-I on hexose transport by Sertoli cells.Crossref | GoogleScholarGoogle Scholar | 3882401PubMed |
Naville, D., Chatelain, P. G., Avallet, O., and Saez, J. M. (1990). Control of production of insulin-like growth factor I by pig Leydig and Sertoli cells cultured alone or together. Cell–cell interactions. Mol. Cell. Endocrinol. 70, 217–224.
| Control of production of insulin-like growth factor I by pig Leydig and Sertoli cells cultured alone or together. Cell–cell interactions.Crossref | GoogleScholarGoogle Scholar | 2113875PubMed |
Nygard, A. B., Jorgensen, C. B., Cirera, S., and Fredholm, M. (2007). Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR. BMC Mol. Biol. 8, 67.
| Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR.Crossref | GoogleScholarGoogle Scholar | 17697375PubMed |
Obr, A. E., Kumar, S., Chang, Y.-J., Bulatowicz, J. J., Barnes, B. J., Birge, R. B., Lazzarino, D. A., Gallagher, E., LeRoith, D., and Wood, T. L. (2018). Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment. Breast Cancer Res. 20, 138.
| Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment.Crossref | GoogleScholarGoogle Scholar | 30458886PubMed |
Orth, J. M. (1982). Proliferation of Sertoli cells in fetal and postnatal rats: a quantitative autoradiographic study. Anat. Rec. 203, 485–492.
| Proliferation of Sertoli cells in fetal and postnatal rats: a quantitative autoradiographic study.Crossref | GoogleScholarGoogle Scholar | 7137603PubMed |
Orth, J. M., Gunsalus, G. L., and Lamperti, A. A. (1988). Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 122, 787–794.
| Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development.Crossref | GoogleScholarGoogle Scholar | 3125042PubMed |
Pitetti, J. L., Calvel, P., Zimmermann, C., Conne, B., Papaioannou, M. D., Aubry, F., Cederroth, C. R., Urner, F., Fumel, B., Crausaz, M., Docquier, M., Herrera, P. L., Pralong, F., Germond, M., Guillou, F., Jégou, B., and Nef, S. (2013). An essential role for insulin and IGF1 receptors in regulating Sertoli cell proliferation, testis size, and FSH action in mice. Mol. Endocrinol. 27, 814–827.
| An essential role for insulin and IGF1 receptors in regulating Sertoli cell proliferation, testis size, and FSH action in mice.Crossref | GoogleScholarGoogle Scholar | 23518924PubMed |
Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y. L., and Schulze, A. (2008). SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236.
| SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.Crossref | GoogleScholarGoogle Scholar | 18762023PubMed |
Rawlings, N. C., Hafs, H. D., and Swanson, L. V. (1972). Testicular and blood plasma androgens in Holstein bulls from birth through puberty. J. Anim. Sci. 34, 435–440.
| Testicular and blood plasma androgens in Holstein bulls from birth through puberty.Crossref | GoogleScholarGoogle Scholar | 5010632PubMed |
Rozman, D. (2000). Lanosterol 14alpha-demethylase (CYP51) – a cholesterol biosynthetic enzyme involved in production of meiosis activating sterols in oocytes and testis – a minireview. Pflügers Archiv. 439, r056–r057.
| Lanosterol 14alpha-demethylase (CYP51) – a cholesterol biosynthetic enzyme involved in production of meiosis activating sterols in oocytes and testis – a minireview.Crossref | GoogleScholarGoogle Scholar | 28176073PubMed |
Salic, A., and Mitchison, T. J. (2008). A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc. Natl Acad. Sci. USA 105, 2415–2420.
| A chemical method for fast and sensitive detection of DNA synthesis in vivo.Crossref | GoogleScholarGoogle Scholar | 18272492PubMed |
Schneider, C. A., Rasband, W. S., and Eliceiri, K. W. (2012). NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675.
| NIH Image to ImageJ: 25 years of image analysis.Crossref | GoogleScholarGoogle Scholar | 22930834PubMed |
Setchell, B. P. (1980). The functional significance of the blood–testis barrier. J. Androl. 1, 3–10.
| The functional significance of the blood–testis barrier.Crossref | GoogleScholarGoogle Scholar |
Singh, B., and Armstrong, D. T. (1997). Insulin-like growth factor-1, a component of serum that enables porcine cumulus cells to expand in response to follicle-stimulating hormone in vitro. Biol. Reprod. 56, 1370–1375.
| Insulin-like growth factor-1, a component of serum that enables porcine cumulus cells to expand in response to follicle-stimulating hormone in vitro.Crossref | GoogleScholarGoogle Scholar | 9166687PubMed |
Singh, P., Saxena, R., Srinivas, G., Pande, G., and Chattopadhyay, A. (2013). Cholesterol biosynthesis and homeostasis in regulation of the cell cycle. PLoS One 8, e58833.
| Cholesterol biosynthesis and homeostasis in regulation of the cell cycle.Crossref | GoogleScholarGoogle Scholar | 24312505PubMed |
Smith, T. M., Gilliland, K., Clawson, G. A., and Thiboutot, D. (2008). IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J. Invest. Dermatol. 128, 1286–1293.
| IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway.Crossref | GoogleScholarGoogle Scholar | 17989724PubMed |
Taniguchi, C. M., Emanuelli, B., and Kahn, C. R. (2006). Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96.
| Critical nodes in signalling pathways: insights into insulin action.Crossref | GoogleScholarGoogle Scholar | 16493415PubMed |
Ullrich, A., and Schlessinger, J. (1990). Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212.
| Signal transduction by receptors with tyrosine kinase activity.Crossref | GoogleScholarGoogle Scholar | 2158859PubMed |
Vannelli, B. G., Barni, T., Orlando, C., Natali, A., Serio, M., and Balboni, G. C. (1988). Insulin-like growth factor-1 (IGF-I) and IGF-I receptor in human testis: an immunohistochemical study. Fertil. Steril. 49, 666–669.
| Insulin-like growth factor-1 (IGF-I) and IGF-I receptor in human testis: an immunohistochemical study.Crossref | GoogleScholarGoogle Scholar | 2965033PubMed |
Weber, J. E., Russell, L. D., Wong, V., and Peterson, R. N. (1983). Three-dimensional reconstruction of a rat Stage V Sertoli cell: II. Morphometry of Sertoli–Sertoli and Sertoli–germ-cell relationships. Am. J. Anat. 167, 163–179.
| Three-dimensional reconstruction of a rat Stage V Sertoli cell: II. Morphometry of Sertoli–Sertoli and Sertoli–germ-cell relationships.Crossref | GoogleScholarGoogle Scholar | 6613902PubMed |
Yamauchi, Y., Furukawa, K., Hamamura, K., and Furukawa, K. (2011). Positive Feedback Loop Between PI3K–Akt–mTORC1 signaling and the lipogenic pathway boosts Akt signaling: induction of the lipogenic pathway by a melanoma antigen. Cancer Res. 71, 4989–4997.
| Positive Feedback Loop Between PI3K–Akt–mTORC1 signaling and the lipogenic pathway boosts Akt signaling: induction of the lipogenic pathway by a melanoma antigen.Crossref | GoogleScholarGoogle Scholar | 21632551PubMed |
Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T. L. (2012). Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 13, 134.
| Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction.Crossref | GoogleScholarGoogle Scholar | 22708584PubMed |
Zhang, W., Haines, B. B., Efferson, C., Zhu, J., Ware, C., Kunii, K., Tammam, J., Angagaw, M., Hinton, M. C., Keilhack, H., Paweletz, C. P., Zhang, T., Winter, C., Sathyanarayanan, S., Cheng, J., Zawel, L., Fawell, S., Gilliland, G., and Majumder, P. K. (2012). Evidence of mTOR activation by an AKT-independent mechanism provides support for the combined treatment of PTEN-deficient prostate tumors with mTOR and AKT inhibitors. Transl. Oncol. 5, 422–429.
| Evidence of mTOR activation by an AKT-independent mechanism provides support for the combined treatment of PTEN-deficient prostate tumors with mTOR and AKT inhibitors.Crossref | GoogleScholarGoogle Scholar | 23323157PubMed |
Zhou, P., Baumgarten, S. C., Wu, Y., Bennett, J., Winston, N., Hirshfeld-Cytron, J., and Stocco, C. (2013). IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells. Mol. Endocrinol. 27, 511–523.
| IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells.Crossref | GoogleScholarGoogle Scholar | 23340251PubMed |
