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1. La vía canónica PI3K/AKT/mTOR y sus alteraciones en cáncer.

Author

F., Aldecoa and J., Ávila

Abstract

The PI3K/AKT/mTOR pathway is involved in multiple cellular processes which are essential for the cells. Some genetic mutations of the components of this pathway have been associated with various human diseases, the most important of which are breast, thyroid and endometrium carcinomas; glioblastoma multiforme; prostate cancer and lymphomas. The PI3K/AKT/mTOR canonical pathway has been extensively studied in recent years. However, as the complexity of its main components and their correlation with the components of other pathways are increasing, it is important to update from time to time the available information to understand this mechanism. Furthermore, many trials have been conducted with selective medicines aimed to look for a more intelligent treatment for diseases associated with alterations in this pathway. Therefore, we review this transduction pathway to take a close look at its functioning and alterations, and to list some promising molecules for future treatments. [ABSTRACT FROM AUTHOR]

Published
2021
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2. The PI3K/AKT/mTOR canonical pathway and its alterations in cancer

Author

FRANKLIN ALDECOA and JACK JUAN AVILA VELASQUEZ

Subjects
TOR serine-threonine kinases, Applied Mathematics, General Mathematics, Proteínas proto-oncogénicas c-akt, Neoplasms, Fosfatidilinositol 3-quinasa, Proto-oncogene proteins c-akt, Cáncer, Serina-treonina quinasas TOR, Phosphatidylinositol 3-kinase
Abstract

La vía PI3K/AKT/mTOR participa en múltiples procesos celulares fundamentales para la célula. Algunas mutaciones genéticas de los componentes de esta vía se han asociado a diversas enfermedades humanas: las más importantes son los carcinomas de mama, tiroides y endometrio, el glioblastoma multiforme, el cáncer de próstata y los linfomas. La vía canónica PI3K/AKT/mTOR se ha estudiado ampliamente en los últimos años. Sin embargo, el conocimiento de la complejidad de sus componentes principales y su interrelación con los elementos de otras vías va en aumento. Por ello, es importantes actualizar cada cierto tiempo la información disponible para la comprensión de este mecanismo. Así mismo, se están y se han desarrollado numerosos ensayos con medicinas selectivas en búsqueda de un tratamiento más inteligente para las enfermedades asociadas a alteraciones de esta vía. Por tanto, realizamos una revisión de esta vía de transducción con el objetivo de tener una visión cercana de su funcionamiento, sus alteraciones y enumerar algunas moléculas promisorias para ser utilizadas en futuros tratamientos. The PI3K/AKT/mTOR pathway is involved in multiple cellular processes which are essential for the cells. Some genetic mutations of the components of this pathway have been associated with various human diseases, the most important of which are breast, thyroid and endometrium carcinomas; glioblastoma multiforme; prostate cancer and lymphomas. The PI3K/AKT/mTOR canonical pathway has been extensively studied in recent years. However, as the complexity of its main components and their correlation with the components of other pathways are increasing, it is important to update from time to time the available information to understand this mechanism. Furthermore, many trials have been conducted with selective medicines aimed to look for a more intelligent treatment for diseases associated with alterations in this pathway. Therefore, we review this transduction pathway to take a close look at its functioning and alterations, and to list some promising molecules for future treatments. Revisión por pares

Published
2021

3. La vía canónica PI3K/AKT/mTOR y sus alteraciones en cáncer

Author

Aldecoa, F and Ávila, J

Subjects
TOR serine-threonine kinases, Proteínas proto-oncogénicas c-akt, Neoplasms, Fosfatidilinositol 3-quinasa, Proto-oncogene proteins c-akt, Cáncer, Serina-treonina quinasas TOR, Phosphatidylinositol 3-kinase
Abstract

The PI3K/AKT/mTOR pathway is involved in multiple cellular processes which are essential for the cells. Some genetic mutations of the components of this pathway have been associated with various human diseases, the most important of which are breast, thyroid and endometrium carcinomas; glioblastoma multiforme; prostate cancer and lymphomas. ThePI3K/AKT/mTOR canonical pathway has been extensively studied in recent years. However, as the complexity of its main components and their correlation with the components of other pathways are increasing, it is important to update fromtime to time the available information to understand this mechanism. Furthermore, many trials have been conducted with selective medicines aimed to look for a more intelligent treatment for diseases associated with alterations in this pathway. Therefore, we review this transduction pathway to take a close look at its functioning and alterations, and to list some promising molecules for future treatments. La vía PI3K/AKT/mTOR participa en múltiples procesos celulares fundamentales para la célula. Algunas mutaciones genéticas de los componentes de esta vía se han asociado a diversas enfermedades humanas: las más importantes son los carcinomas de mama, tiroides y endometrio, el glioblastoma multiforme, el cáncer de próstata y los linfomas. La vía canónica PI3K/AKT/mTOR se ha estudiado ampliamente en los últimos años. Sin embargo, el conocimiento de la complejidad de sus componentes principales y su interrelación con los elementos de otras vías va en aumento. Por ello, es importantes actualizar cada cierto tiempo la información disponible para la comprensión de este mecanismo. Así mismo, se están y se han desarrollado numerosos ensayos con medicinas selectivas en búsqueda de un tratamiento más inteligente para las enfermedades asociadas a alteraciones de esta vía. Por tanto, realizamos una revisión de esta vía de transducción con el objetivo de tener una visión cercana de su funcionamiento, sus alteraciones y enumerar algunas moléculas promisorias para ser utilizadas en futuros tratamientos.

Published
2021

4. La vía canónica PI3K/AKT/mTOR y sus alteraciones en cáncer

Author

Aldecoa Bedoya, Franklin, Ávila, J., Aldecoa Bedoya, Franklin, and Ávila, J.

Abstract

The PI3K/AKT/mTOR pathway participates in multiple fundamental cellular processes for the cell, the alterations in the genes of the proteins related to this pathway can be the beginning of a disease such as cancer. The canonical pathway of this pathway, whose main components and their interrelation with other elements is quite complex, has been extensively studied in recent years, however, it remains to be investigated and learned. There are several genetic mutations in each of the components of this pathway, which have been associated with various human diseases, likewise, some trials have been carried out with selective medicines in search of a more intelligent treatment, with different results. Therefore, we carry out a review of this transduction pathway, important in the genesis of some types of human cancers, with the idea of ​​having a close view of its functioning, its alterations, the search for new promising molecules for its treatment and a possible explanation of why the experimentation has not been as fruitful, so far, as expected., La vía PI3K/AKT/mTOR participa en múltiples procesos celulares fundamentales para la célula. Algunas mutaciones genéticas de los componentes de esta vía se han asociado a diversas enfermedades humanas: las más importantes son los carcinomas de mama, tiroides y endometrio, el glioblastoma multiforme, el cáncer de próstata y los linfomas. La vía canónica PI3K/AKT/mTOR se ha estudiado ampliamente en los últimos años. Sin embargo, el conocimiento de la complejidad de sus componentes principales y su interrelación con los elementos de otras vías va en aumento. Por ello, es importantes actualizar cada cierto tiempo la información disponible para la comprensión de este mecanismo. Así mismo, se están y se han desarrollado numerosos ensayos con medicinas selectivas en búsqueda de un tratamiento más inteligente para las enfermedades asociadas a alteraciones de esta vía. Por tanto, realizamos una revisión de esta vía de transducción con el objetivo de tener una visión cercana de su funcionamiento, sus alteraciones y enumerar algunas moléculas promisorias para ser utilizadas en futuros tratamientos.

Published
2021

5. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

Author

Ferrín, Gustavo, Guerrero, Marta, Amado, Víctor, Rodríguez-Perálvarez, Manuel, De la Mata, Manuel, [Ferrín,G, Guerrero,M, Amado,V, Rodríguez-Perálvarez,M, De la Mata,M] Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain. [Ferrín,G, De la Mata,M] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Córdoba, Spain. [Guerrero,M, De la Mata,M] Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, Córdoba, Spain., and This work was supported by the research project PI18/01736 integrated into the Plan Estatal de I+D+I 2013-2016 and co-financed by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación and the Fondo Europeo de Desarrollo Regional (FEDER).

Subjects
Sirolimus, Liver transplantation, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms::Carcinoma, Hepatocellular [Medical Subject Headings], Hepatocellular carcinoma, Trasplante de hígado, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms [Medical Subject Headings], Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal Transduction [Medical Subject Headings], Diseases::Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [Medical Subject Headings], Sorafenib, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Lactones::Macrolides::Sirolimus [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], mTOR, Everolimus, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::TOR Serine-Threonine Kinases [Medical Subject Headings], Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings], Serina-treonina quinasas TOR, Carcinoma hepatocelular
Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies. Yes

Published
2020

6. Direct regulation of fibroblast growth factor 23 by energy intake through mTOR

Author

Mariano Rodriguez, Carmen Pineda, Ignacio González López, Escolastico Aguilera-Tejero, Rafael Rios, Ana I. Raya, Angela Vidal, Juan R. Muñoz-Castañeda, [Vidal,A, Rios,R, Pineda,C, Lopez,I, Aguilera-Tejero,E, Raya,AI] Department of Animal Medicine and Surgery, University of Cordoba, Campus Universitario Rabanales, Cordoba, Spain. [Vidal,A, Muñoz-Castañeda,JR, Rodriguez,M, Raya,AI] Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain., and The work reported here was supported by a Spanish Government Grant from the Instituto de Salud Carlos III (PI17/00169) with co-financing from European Funds.

Subjects
0301 basic medicine, Fibroblast growth factor 23, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose [Medical Subject Headings], lcsh:Medicine, 030204 cardiovascular system & hematology, Intestinal absorption, Endocrinology, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, Wistar [Medical Subject Headings], lcsh:Science, Serina-treonina quinasas TOR, Factores de crecimiento de fibroblastos 23, Multidisciplinary, biology, Chemistry, TOR Serine-Threonine Kinases, Ingestión de energía, Endocrine system and metabolic diseases, Phosphorus, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Energy Intake [Medical Subject Headings], Female, Mannitol, medicine.drug, medicine.medical_specialty, RNA, messenger, Cells, Article, 03 medical and health sciences, Ratas, Células, In vivo, Internal medicine, Cell Line, Tumor, medicine, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::TOR Serine-Threonine Kinases [Medical Subject Headings], Animals, Rats, Wistar, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Messenger RNA, ARN mensajero, lcsh:R, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Fibroblast Growth Factors [Medical Subject Headings], In vitro, Rats, Fibroblast Growth Factors, stomatognathic diseases, Fibroblast Growth Factor-23, 030104 developmental biology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats [Medical Subject Headings], Glucose, Check Tags::Female [Medical Subject Headings], Glucosa, Chemicals and Drugs::Inorganic Chemicals::Elements::Phosphorus [Medical Subject Headings], biology.protein, lcsh:Q, Energy Intake
Abstract

To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.

Published
2020

7. Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer

Author

Rodríguez-Hernández, María A., Cruz, Patricia de la, López-Grueso, M. José, Navarro-Villarán, Elena, Requejo-Aguilar, Raquel, Castejón Vega, Beatriz, Negrete, María, Gallego, Paloma, Vega-Ochoa, Álvaro, Victor, Víctor M., Cordero, Mario D., Campo, José A. del, Bárcena, J. Antonio, Padilla, Alicia C., Muntané, Jordi, [Rodríguez-Hernández,A, de la Cruz-Ojeda,P, Navarro-Villarán,E, Negrete,M, Vega-Ochoa,A, Muntané,J] Institute of Biomedicine of Seville (IBiS), IBiS/Hospital University 'Virgen del Rocío'/CSIC/University of Seville, Seville, Spain. [Rodríguez-Hernández,A, Victor,VM, Muntané,J] Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. [López-Grueso,MJ, Requejo-Aguilar,R, Bárcena,JA, Padilla,CA] Department of Biochemistry and Molecular Biology, University of Cordoba, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain. [Castejón-Vega,B, Cordero,MD] Research Laboratory, Oral Medicine Department, University of Seville, Seville, Spain. [Gallego,P, Del Campo,JA] Unit for the Clinical Management of Digestive Diseases, Hospital University 'Nuestra Señora de Valme', Sevilla, Spain. [Victor,VM] Service of Endocrinology and Nutrition, Hospital University 'Doctor Peset', Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain. [Victor,VM] Department of Physiology, University of Valencia, Valencia, Spain. [Cordero,MD] Department of Physiology, Institute of Nutrition and Food Technology 'José Mataix', Biomedical Research Center (CIBM), University of Granada, Armilla, Spain. [Muntané,J] Department of General Surgery, Hospital University 'Virgen del Rocío'/IBiS/CSIC/University of Seville, Seville, Spain., This study was funded by Institute of Health Carlos III (ISCiii) (PI16/00090, PI19/00838 and PI19/01266), Spanish Ministry of Economy and Competitiveness (BFU2016-80006-P), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264), Andalusian Ministry of Equality, Health and Social Policies (PI-0198-2016) and Valencian Ministry of Education, Culture and Sports (PROMETEO/2019/027). P de la C-O was supported by FPU predoctoral fellowship (FPU17/00026) from Spanish Ministry of Education, Culture and Sports. E N-V was supported by the the predoctoral i-PFIS IIS-enterprise contract in science and technologies in health (IFI18/00014) from ISCiii., Instituto de Salud Carlos III, Junta de Andalucía, Generalitat Valenciana, Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), European Commission, and Ministerio de Economía y Competitividad (España)

Subjects
Cell death, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [Medical Subject Headings], PGC-1α, Autofagia, Phenomena and Processes::Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment [Medical Subject Headings], Estrés del retículo endoplásmico, Diseases::Neoplasms [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::Proto-Oncogene Proteins c-akt [Medical Subject Headings], Muerte celular, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings], Oxidación-reducción, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Redox status, Autophagy, Endoplasmic reticulum stress, mTOR, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagy [Medical Subject Headings], Serina-treonina quinasas TOR, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Phosphatidylinositol 3-Kinases::Phosphatidylinositol 3-Kinase [Medical Subject Headings], Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria [Medical Subject Headings]
Abstract

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages. There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments. This study was funded by Institute of Health Carlos III (ISCiii) (PI16/00090, PI19/00838 and PI19/01266), Spanish Ministry of Economy and Competitiveness (BFU2016-80006-P), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264), Andalusian Ministry of Equality, Health and Social Policies (PI-0198-2016) and Valencian Ministry of Education, Culture and Sports (PROMETEO/2019/027). P de la C-O was supported by FPU predoctoral fellowship (FPU17/00026) from Spanish Ministry of Education, Culture and Sports. E N-V was supported by the the predoctoral i-PFIS IIS-enterprise contract in science and technologies in health (IFI18/00014) from ISCiii. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERcv), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCiii and co-financed by European Regional Development Fund (ERDF) "A way to achieve Europe" for their financial support.

Published
2020

8. Characterization of an eutherian gene cluster generated after transposon domestication identifies Bex3 as relevant for advanced neurological functions

Author

Pol Cuscó, Demian Burguera, Salvatore D'Aniello, Cristina Vicente-García, Bru Cormand, Enrique Navas-Perez, José Luis Ferran, Jordi Garcia-Fernàndez, Carlos Herrera-Úbeda, Marta Alaiz-Noya, Rafael Falcón-Moya, Angel M. Carrión, Serena Mirra, Irene Suárez-Pereira, Gemma Marfany, Fausto Ulloa, Eduardo Soriano, Noèlia Fernàndez-Castillo, Ester Antón-Galindo, Jaime J. Carvajal, Antonio Rodríguez-Moreno, Macarena López-Mayorga, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Junta de Andalucía, Centro de Investigación Biomédica en Red Enfermedades Raras (España), [Navas-Pérez,E, Mirra,S, Burguera,D, Fernàndez-Castillo,N, Antón-Galindo,E, Herrera-Úbeda,C, Cormand,B, Marfany,G, Garcia-Fernàndez,J] Department of Genetics, Microbiology and Statistics, Faculty of Biology, and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona, Spain. [Vicente-García,C, López-Mayorga,M, Carvajal,JJ] Centro Andaluz de Biología del Desarrollo, CSIC-UPO-JA, Universidad Pablo de Olavide, Sevilla, Spain. [Mirra,S, Ulloa,F, Soriano,E] Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, Barcelona, Spain. [Mirra,S, Marfany,G] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Mirra,S, Soriano,E] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Burguera,D] Department of Zoology, Charles University, Prague, Czech Republic. [Fernàndez-Castillo,N, Marfany,G] Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain. [Ferrán,JL] Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain. [Alaiz-Noya,M, Suárez-Pereira,I, Falcón-Moya,R, Rodríguez-Moreno,A, Carrión,AM] Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Sevilla, Spain. [Alaiz-Noya,M] Present Address: Instituto de Neurociencias de Alicante (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas), Alicante, Spain. [Suárez-Pereira,I] Present Address: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Neuropsychopharmacology and psychobiology research group, UCA, INiBICA, Cádiz, Spain. [Cuscó,P] Genome Architecture, Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Spain. [Cuscó,P] Universitat Pompeu Fabra (UPF), Barcelona, Spain. [D'Aniello,S] Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Naples, Italy. [Soriano,E] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., and Major financial support for this research was received from Spanish 'Ministerio de Ciencia, Innovación y Universidades.' Grants BFU2015-68655-P and BFU2017-861152-P to J.G.F., RTI2018-100968-B-I00, 2017-SGR-738, H2020/2014-2020 under grant agreements n°667302, n°643051, and n°728018 to B.C., PGC2018-098229-B-I00 to J.L.F., BES-2016-077374 to E.A.-G., CVI-7290 Junta de Andalucía to A.R.M., SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER) to G.M., Institutional Grant MDM-2016-0687 (Maria de Maeztu Excellence Unit, Department of Gene Regulation and Morphogenesis at CABD) and BFU2017-83150-P to J.J.C, BFU2017-89780-R and P12-CTS-2257 to A.M.C. and SAF2016-76340-R and María de Maeztu Excellence Unit, Institute of Neurosciences to E.S.. E.N.P. held an FPI pre-doctoral fellowship (Spanish 'Ministerio de Ciencia, Innovación y Universidades'). S.M. was first supported by a contract with the 'Centro de Investigación Biomédica en Enfermedades Neurodegenerativas,' and later by 'Centro de Investigación Biomédica en Red de Enfermedades Raras' (CIBERER). N.F.C. is also under contract by CIBERER. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available at http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust.

Subjects
Bex3, Tceal, Placenta, Autism, Genome, Neurodevelopmental disorders, Familia de multigenes, Domestication, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Human genetics, Pregnancy, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins [Medical Subject Headings], Gene duplication, Gene cluster, Organisms::Eukaryota::Animals [Medical Subject Headings], Autism spectrum disorder, Genetic novelty, lcsh:QH301-705.5, Serina-treonina quinasas TOR, Phylogeny, Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Reproductive Physiological Processes::Reproduction::Pregnancy [Medical Subject Headings], Mice, Knockout, 0303 health sciences, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins [Medical Subject Headings], Genètica humana, Eutheria, TOR Serine-Threonine Kinases, Brain, Nuclear Proteins, DNA-Binding Proteins, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, Knockout [Medical Subject Headings], Multigene Family, Placental mammals, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins [Medical Subject Headings], mTOR, Female, Transposon domestication, Transposable element, lcsh:QH426-470, Psychiatry and Psychology::Mental Disorders::Mental Disorders Diagnosed in Childhood::Child Development Disorders, Pervasive::Autistic Disorder [Medical Subject Headings], Nerve Tissue Proteins, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::Apoptosis Regulatory Proteins [Medical Subject Headings], Biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings], Evolution, Molecular, 03 medical and health sciences, Trastornos del neurodesarrollo, Animals, Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::TOR Serine-Threonine Kinases [Medical Subject Headings], Allele, Gene, 030304 developmental biology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Research, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Anatomy::Embryonic Structures::Placenta [Medical Subject Headings], Phenomena and Processes::Biological Phenomena::Biological Processes::Biological Evolution::Evolution, Molecular [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic::Gene Silencing::CRISPR-Cas Systems [Medical Subject Headings], Mice, Inbred C57BL, lcsh:Genetics, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Interspersed Repetitive Sequences::DNA Transposable Elements [Medical Subject Headings], lcsh:Biology (General), Check Tags::Female [Medical Subject Headings], Evolutionary biology, DNA Transposable Elements, Euterios, Phenomena and Processes::Genetic Phenomena::Phylogeny [Medical Subject Headings], Trastorno del espectro autista, CRISPR-Cas Systems, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings], Autisme, Apoptosis Regulatory Proteins, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Multigene Family [Medical Subject Headings], 030217 neurology & neurosurgery, Transcription Factors
Abstract

[Background]: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood., [Results]: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes., [Conclusions]: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders., Major financial support for this research was received from Spanish “Ministerio de Ciencia, Innovación y Universidades.” Grants BFU2015-68655-P and BFU2017-861152-P to J.G.F., RTI2018-100968-B-I00, 2017-SGR-738, H2020/2014-2020 under grant agreements n°667302, n°643051, and n°728018 to B.C., PGC2018-098229-B-I00 to J.L.F., BES-2016-077374 to E.A.-G., CVI-7290 Junta de Andalucía to A.R.M., SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER) to G.M., Institutional Grant MDM-2016-0687 (Maria de Maeztu Excellence Unit, Department of Gene Regulation and Morphogenesis at CABD) and BFU2017-83150-P to J.J.C, BFU2017-89780-R and P12-CTS-2257 to A.M.C. and SAF2016-76340-R and María de Maeztu Excellence Unit, Institute of Neurosciences to E.S.. E.N.P. held an FPI pre-doctoral fellowship (Spanish “Ministerio de Ciencia, Innovación y Universidades”). S.M. was first supported by a contract with the “Centro de Investigación Biomédica en Enfermedades Neurodegenerativas,” and later by “Centro de Investigación Biomédica en Red de Enfermedades Raras” (CIBERER). N.F.C. is also under contract by CIBERER.

Published
2020

9. Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

Author

Enrique Saez, Joan Vendrell, Oscar Yanes, Sonia Fernández-Veledo, Marta Montori-Grau, Anna M. Gómez-Foix, Miriam Ejarque, Carolina Serena, Victoria Ceperuelo-Mallafré, Lourdes Garrido-Sánchez, Prasanth Puthanveetil, Miguel Angel Rodríguez, Catalina Núñez-Roa, Xavier Duran, Pablo M. Garcia-Roves, Kelly Roche, Francisco J. Tinahones, Alan R. Saltiel, [Ceperuelo-Mallafré,V, Ejarque,M, Serena,C, Núñez-Roa,C, Roche,K, Vendrell,J, Fernández-Veledo,S] Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain. [Ceperuelo-Mallafré,V, Durán,X, Montori-Grau,M, Rodríguez,MA, Yánes,O, Gómez-Foix,AM, Fernández-Veledo,S] CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. [Montori-Grau,M] Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. [Rodríguez,MA] Centre for Omic Sciences (COS), Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain. [Yanes,O] Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain. [Puthanveetil,P, Saltiel,AR] Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. [Garrido-Sánchez,L, Tinahones,FJ] Hospital Universitario Virgen de la Victoria, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Universidad de Málaga, IBIMA, Spain. [Garrido-Sánchez,L, Tinahones,FJ] CIBER de Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. [Sáez,E] Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. [García-Roves,PM] Departamento de Ciencias Fisiológicas II, Facultad de Medicina, Universitat de Barcelona, Barcelona, Spain., and This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2012-36186 to SF-V, PI14/00228 to JV and PI12/02355 to FJT). The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. SF-V and LG-S acknowledge support from the 'Miguel Servet' tenure-track program (CP10/00438 and CP13/00188, respectively) from the Fondo de Investigación Sanitaria (FIS) co-financed by the European Regional Development Fund (ERDF).

Subjects
0301 basic medicine, Macròfags, Physiology, Macrophage, Obesidad, Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Mass Index [Medical Subject Headings], Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose [Medical Subject Headings], Adipose tissue, White adipose tissue, Índice de masa corporal, Grasa subcutánea, Energy homeostasis, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, Adipocyte, Organisms::Eukaryota::Animals [Medical Subject Headings], Glucógeno sintasa, Masculino, Glycogen, Ratón, Humanos, Estrés fisiológico, Anatomy::Cells::Connective Tissue Cells::Adipocytes [Medical Subject Headings], Obesitat, Original Article, medicine.symptom, Anatomy::Tissues::Connective Tissue::Adipose Tissue::Adipose Tissue, White::Subcutaneous Fat [Medical Subject Headings], Resistència a la insulina, medicine.medical_specialty, lcsh:Internal medicine, Check Tags::Male [Medical Subject Headings], Inflammation, Context (language use), Biology, Resistencia a la insulina, Serina-Treonina Quinasas TOR, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Spectrum Analysis::Magnetic Resonance Spectroscopy [Medical Subject Headings], 03 medical and health sciences, Insulin resistance, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance [Medical Subject Headings], Autofàgia, Internal medicine, Adipocitos, medicine, Autophagy, Obesity, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagy [Medical Subject Headings], lcsh:RC31-1245, Molecular Biology, Espectrometría de Masas, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Macrophages, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Glycosyltransferases::Hexosyltransferases::Glucosyltransferases::Glycogen Synthase [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Physiological Processes::Stress, Physiological [Medical Subject Headings], Espectroscopía de Resonancia Magnética, Cell Biology, medicine.disease, Glicogen, 030104 developmental biology, Endocrinology, chemistry, Animales, Glucosa, Biochemistry and Cell Biology, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::TOR Serine-Threonine Kinases [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Mass Spectrometry [Medical Subject Headings]
Abstract

Objective Glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance. Methods We studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts. Results We show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated with BMI and leptin expression. Conclusion Our data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity., Highlights • Hypoxia redirects extracellular glucose to glycogen synthesis in human adipocytes. • Glycogen modifies the endocrine function of adipocytes and induces insulin resistance. • Glycogen stimulates leptin secretion through an autophagy-dependent mechanism. • Enforced glycogen accumulation in macrophages promotes M1 polarization. • Obesity is associated with higher GS expression and glycogen stores in adipose tissue.

Published
2015

10. Genetic variability of the mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC)

Author

Laudina Rodríguez, Anika Hüsing, Isabelle Romieu, Rudolf Kaaks, Naomi E. Allen, Heiner Boeing, Federico Canzian, Carlotta Sacerdote, Kim Overvad, Núria Sala, David G. Cox, Elio Riboli, José María Huerta, Henk J. van Kranen, Lucie Dostal, H. Bas Bueno-de-Mesquita, Jane Nautrup Østergaard, Afshan Siddiq, Ruth C. Travis, María José Sánchez, Nerea Larrañaga, Anne Tjønneland, Angelika Stein, Göran Hallmans, Nicholas J. Wareham, Daniele Campa, Antonia Trichopoulou, Nina Roswall, Rosario Tumino, Pagona Lagiou, Mazda Jenab, Dimitrios Trichopoulos, Aurelio Barricarte, Mattias Johansson, Kay-Tee Khaw, Domenico Palli, Tobias Pischon, Sabina Sieri, [Campa, Daniele, Huesing, Anika, Stein, Angelika, Dostal, Lucie, Canzian, Federico, Kaaks, Rudolf] German Canc Res Ctr, Heidelberg, Germany. [Boeing, Heiner, Pischon, Tobias] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Tjonneland, Anne, Roswall, Nina] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Overvad, Kim, Ostergaard, Jane Nautrup] Aarhus Univ Hosp, Dept Cardiol, Cardiovasc Res Ctr, Aalborg Hosp, Aalborg, Denmark. [Overvad, Kim, Ostergaard, Jane Nautrup] Aarhus Univ, Dept Epidemiol, Sch Publ Hlth, DK-8000 Aarhus C, Denmark. [Rodriguez, Laudina] Hlth & Hlth Care Serv Council, Publ Hlth & Participat Directorate, Asturias, Spain. [Sala, Nuria] ICO IDIBELL, Barcelona, Spain. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada, Spain. [Sanchez, Maria-Jose, Larranaga, Nerea, Maria Huerta, Jose, Barricarte, Aurelio] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Madrid, Spain. [Larranaga, Nerea] Basque Govt, Publ Hlth Dept Gipuzkoa, Gipuzkoa, Spain. [Maria Huerta, Jose] Murcia Reg Hlth Author, Dept Epidemiol, Murcia, Spain. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge, England. [Wareham, Nicholas] MRC Epidemiol Unit, Cambridge, England. [Travis, Ruth C., Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Lagiou, Pagona, Trichopoulou, Antonia] Univ Athens, Sch Med, WHO Collaborating Ctr Food & Nutr Policies, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Lagiou, Pagona, Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Sieri, Sabina] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Canc Registry, Ragusa, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Histopathol Unit, Ragusa, Italy. [Sacerdote, Carlotta] Ctr Canc Prevent CPO Piemonte, Turin, Italy. [Sacerdote, Carlotta] Human Genet Fdn HuGeF, Turin, Italy. [van Kranen, Henk, Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, Ctr Nutr & Hlth CVG, Bilthoven, Netherlands. [Hallmans, Goran, Johansson, Mattias] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Johansson, Mattias, Romieu, Isabelle, Jenab, Mazda] Int Agcy Res Canc, F-69372 Lyon, France. [Cox, David G., Siddiq, Afshan, Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, London, England. [Cox, David G.] Ctr Leon Berard, INSERM, F-69373 Lyon, France., Specific results of this study were obtained with financial support from the US Army Medical Research and Material Command (W81XWH-05-1-0156). http://cdmrp.army.mil/pcrp/default.shtml. The EPIC study was funded by 'Europe Against Cancer' Programme of the European Commission (SANCO), Ligue contre le Cancer (France), Société 3M (France), Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Aid, German Cancer Research Center, German Federal Ministry of Education and Research, Danish Cancer Society, Health Research Fund (FIS) of the Spanish Ministry of Health, the participating regional governments and institutions of Spain, Cancer Research UK, Medical Research Council, UK, Hellenic Ministry of Health and Social Solidarity, the Stavros Niarchos Foundation and the Hellenic Health Foundation, Italian Association for Research on Cancer, Italian National Research Council, Dutch Ministry of Public Health, Welfare and Sports (VWS), Dutch Ministry of Health, Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands), Statistics Netherlands, Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane, Sweden, Norwegian Cancer Society, Department of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), German Institute of Human Nutrition Potsdam-Rehbrücke, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Cancer Epidemiology Institute, Department of Cardiology, Aarhus University Hospital, Public Health and Participation Directorate, Health and Health Care Services Council, Catalan Institute of Oncology, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), Granada Cancer Registry, Andalusian School of Public Health [Granada], Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), CIBER de Epidemiología y Salud Pública (CIBERESP), Murcia Regional Health Authority, Public Health Institute of Navarra, School of Clinical Medicine, University of Cambridge [UK] (CAM), Epidemiology Unit, Medical Research Council, Cancer Epidemiology Unit, University of Oxford [Oxford]-Cancer Epidemiology Unit, WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene-Epidemiology and Medical Statistics-Athens Medical School, Department of Hygiene, Epidemiology and Medical Statistics, Harvard School of Public Health, Bureau of Epidemiologic Research, Academy of Athens, Molecular and Nutritional Epidemiology Unit, ISPO-Cancer Research and Prevention Institute, Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Cancer Registry, Civile - M.P.Arezzo Hospital, CPO Piemonte, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Nutrition and Metabolism Section, International Agency for Cancer Research (IACR), Unit of Nutrition, Environment, and Cancer, Equipe 6, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genomics of Common Disease, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Epidemiology and Biostatistics, Imperial College London-Faculty of Medicine-School of public health, Department of Epidemiology and Public Health, Imperial College London, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Aalborg Hospital-Aarhus University Hospital, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública ( CIBERESP ), Andalusian School of Public Health, University of Cambridge [UK] ( CAM ), Azienda Ospedaliera 'Civile M.P.Arezzo', National Institute for Public Health and the Environment [Bilthoven] ( RIVM ), University of Umeå, International Agency for Research on Cancer, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Oncology, Male, MESH: Carcinoma, Epidemiology, protein p53, MESH : Aged, PROTEIN, Genome-wide association study, MESH : Genotype, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, KAPPA-B ACTIVATION, MESH: Genotype, 0302 clinical medicine, PKC-IOTA, Epidemiology of cancer, Multicenter Studies as Topic, TUBEROUS SCLEROSIS, MESH: Genetic Variation, lcsh:Science, MESH : Isoenzymes, 0303 health sciences, MESH: Middle Aged, MESH : Carcinoma, TOR Serine-Threonine Kinases, Cancer Risk Factors, target of rapamycin kinase, MTOR protein, MESH: Case-Control Studies, 3. Good health, 030220 oncology & carcinogenesis, Medicine, Science & Technology - Other Topics, MESH : Genome-Wide Association Study, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], MESH : Prostatic Neoplasms, Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Signal Transduction [Medical Subject Headings], medicine.medical_specialty, MESH : Case-Control Studies, Genotype, Single-nucleotide polymorphism, Variación genética, 03 medical and health sciences, Genetics, Cancer Genetics, Humans, MESH : Middle Aged, human, Biology, mammalian target of rapamycin, Aged, Estudio Multicéntrico, Science & Technology, MESH: Humans, MULTIDISCIPLINARY SCIENCES, lcsh:R, MESH : Humans, Genetic Variation, medicine.disease, MESH : Neoplasms, Genitourinary Tract Tumors, Genetic epidemiology, Cardiovascular and Metabolic Diseases, Case-Control Studies, KINASE-C-IOTA, MESH: Genome-Wide Association Study, MESH: Multicenter Studies as Topic, lcsh:Q, MESH : Genetic Predisposition to Disease, RAPAMYCIN, Lifestyle Causes of Cancer, MESH: Signal Transduction, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Multicenter Studies as Topic [Medical Subject Headings], lcsh:Medicine, Bioinformatics, MESH : Multicenter Studies as Topic, Prostate cancer, Risk Factors, MESH: Risk Factors, Neoplasms, Clinical Epidemiology, MESH: Neoplasms, Protein Kinase C, MESH: Aged, Multidisciplinary, Prostate Cancer, MESH: Genetic Predisposition to Disease, Middle Aged, MESH : Risk Factors, European Prospective Investigation into Cancer and Nutrition, Europe, Isoenzymes, Diseases::Male Urogenital Diseases::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [Medical Subject Headings], Genetic Epidemiology, protein kinase C lambda, MESH: Isoenzymes, MESH : TOR Serine-Threonine Kinases, isoenzyme, Cancer Epidemiology, Signal Transduction, Research Article, MESH : Male, Genetic Causes of Cancer, MESH : Europe, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neoplasias de la Próstata, Genetic polymorphisms, Serina-Treonina Quinasas TOR, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], LUNG-CANCER, MESH : Genetic Variation, Internal medicine, medicine, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::TOR Serine-Threonine Kinases [Medical Subject Headings], Genetic Predisposition to Disease, MESH : Protein Kinase C, PI3K/AKT/mTOR pathway, Genetic Association Studies, MESH: TOR Serine-Threonine Kinases, 030304 developmental biology, MESH : Signal Transduction, COMPLEX, Càncer de pròstata, Polimorfisme genètic, Carcinoma, MTOR protein, human, protein kinase C, Cancer, Prostatic Neoplasms, Cancers and Neoplasms, Human Genetics, MESH: Protein Kinase C, MESH: Male, MAMMALIAN TARGET, MESH: Prostatic Neoplasms, CELL-GROWTH, MESH: Europe, EPIC, Genome-Wide Association Study
Abstract

International audience; The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p

Published
2011

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