المؤلفون: Wen-Ling Chou, Andrea Galmozzi, David Partida, Kevin Kwan, Hui Yeung, Andrew I Su, Enrique Saez

المصدر: PLoS ONE, Vol 8, Iss 8, p e72511 (2013)

مصطلحات موضوعية: Medicine, Science

الوصف: Adipose tissue renewal and obesity-driven expansion of fat cell number are dependent on proliferation and differentiation of adipose progenitors that reside in the vasculature that develops in coordination with adipose depots. The transcriptional events that regulate commitment of progenitors to the adipose lineage are poorly understood. Because expression of the nuclear receptor PPARγ defines the adipose lineage, isolation of elements that control PPARγ expression in adipose precursors may lead to discovery of transcriptional regulators of early adipocyte determination. Here, we describe the identification and validation in transgenic mice of 5 highly conserved non-coding sequences from the PPARγ locus that can drive expression of a reporter gene in a manner that recapitulates the tissue-specific pattern of PPARγ expression. Surprisingly, these 5 elements appear to control PPARγ expression in adipocyte precursors that are associated with the vasculature of adipose depots, but not in mature adipocytes. Characterization of these five PPARγ regulatory sequences may enable isolation of the transcription factors that bind these cis elements and provide insight into the molecular regulation of adipose tissue expansion in normal and pathological states.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3757023?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/7eba34dbb29a47ef9a2c46c976acbc30Test

المؤلفون: Mónica Álvarez-Fernández, María Sanz-Flores, Belén Sanz-Castillo, Salazar Roa, María, David Partida, Elisabet Zapatero-Solana, H. Raza Ali, Eusebio Manchado, Scott Lowe, Todd VanArsdale, David Shields, Carlos Caldas, Miguel Quintela-Fandino, Marcos Malumbres

المساهمون: Marcos Malumbres

مصطلحات موضوعية: Cell cycle, MASTL, PP2A, Biología celular (Biología), 2403 Bioquímica

الوصف: PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit. Despite its critical role in cell cycle progression in multiple organisms, its relevance as a therapeutic target in human cancer and its dependence of PP2A activity is mostly unknown. Here we show that MASTL overexpression predicts poor survival and shows prognostic value in breast cancer patients. MASTL knockdown or knockout using RNA interference or CRISPR/Cas9 systems impairs proliferation of a subset of breast cancer cells. The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. By using a new inducible CRISPR/Cas9 system in breast cancer cells, we show that genetic ablation of MASTL displays a significant therapeutic effect in vivo. All together, these data suggest that the PP2A inhibitory kinase MASTL may have both prognostic and therapeutic value in human breast cancer. ; Depto. de Bioquímica y Biología Molecular ; Fac. de Ciencias Biológicas ; TRUE ; pub

وصف الملف: application/pdf

العلاقة: info:eu-repo/grantAgreement/MINECO//SAF2014-60442-JIN/ES/RELEVANCIA FUNCIONAL DE LA RUTA GREATWALL%2FPP2A EN EL MANTENIMIENTO DE LA ESTABILIDAD GENOMICA: IMPLICACIONES TERAPEUTICAS EN CANCER/; SAF2012-38215; info:eu-repo/grantAgreement/MINECO//SAF2014-57791-REDC/ES/BIOLOGIA DEL CANCER/; OncoCycle Programme (S2010/BMD-2470); MitoSys project; HEALTH-F5-2010-241548); https://hdl.handle.net/20.500.14352/97839Test; Álvarez-Fernández, M., Sanz-Flores, M., Sanz-Castillo, B. et al. Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer. Cell Death Differ (2017). https://doi.org/10.1038/s41418-017-0024-0Test; https://www.nature.com/articles/s41418-017-0024-0Test

الإتاحة: https://doi.org/20.500.14352/97839Test
https://doi.org/10.1038/s41418-017-0024-0Test
https://hdl.handle.net/20.500.14352/97839Test
https://www.nature.com/articles/s41418-017-0024-0Test

المؤلفون: Lola Martínez, David Partida, Javier Muñoz, Aicha El Bakkali, Marianna Trakala, Begoña Hurtado, Pilar Ximénez-Embún, Belén Sanz-Castillo, Ruth Sánchez-Martínez, Pablo García de Frutos, Marcos Malumbres, María Maroto, Mónica Álvarez-Fernández

المساهمون: Ministerio de Ciencia e Innovación (España), Fundacion La Caixa, Comunidad de Madrid, Fundación La Mataró TV3

المصدر: Repisalud
Instituto de Salud Carlos III (ISCIII)

مصطلحات موضوعية: 0301 basic medicine, Blood Platelets, Phosphoprotein phosphatases, Mutation, Missense, Hyperphosphorylation, Chromosome Disorders, Mice, Transgenic, macromolecular substances, Protein Serine-Threonine Kinases, Cell cycle, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Phosphorylation, Cytoskeleton, Mitosis, Actin, Protein kinase C, Chemistry, Kinase, Chromosome Breakage, Thrombosis, General Medicine, Cell Biology, Hematology, Actin cytoskeleton, Thrombocytopenia, Cell biology, Actin Cytoskeleton, 030104 developmental biology, Amino Acid Substitution, 030220 oncology & carcinogenesis, Pseudopodia, Microtubule-Associated Proteins, Signal Transduction, Research Article

الوصف: MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the thrombocytopenia-associated mutation developed thrombocytopenia as a consequence of aberrant activation and survival of platelets. Activation of mutant platelets was characterized by hyper-stabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects. These aberrations were accompanied by abnormal hyper-phosphorylation of multiple components of the actin cytoskeleton and were rescued both in vitro and in vivo by inhibiting upstream kinases such as PKA, PKC, or AMPK. These data reveal an unexpected role of Mastl in actin cytoskeleton dynamics in postmitotic cells, and suggest that the thrombocytopenia-associated mutation in MASTL is a pathogenic dominant mutation that mimics decreased PP2A activity resulting in altered phosphorylation of cytoskeletal regulatory pathways. We thank Peter Storz (Mayo Clinic; Jacksonville, FL) for sharin g reagents and Sheila Rueda for her support with the management of the mouse colony. B.H. and R.S.-M. were supported by the Juan de la Cierva Programme from the Spanish M inistry of Economy and Competitiveness (MINECO). M.T. was supported by Foundation La Caixa. A.E.B. was supported by the Programa de Empleo Juvenil, Comunidad de M adrid. M.A.-F. received a young investigator g rant from MINECO (SAF2014-60442- JIN; co-financed by FEDER funds). P.G.dF. was supported by Fundació la Marató de TV3 (project 080121 and project 20153031). J.M. was supported by the Ramon y Cajal programme (MINECO; RYC-2012-10651). M.M. lab. is supported by grants from the MINE CO (SAF2015- 69920-R), Programa iLUNG from the Comunidad de Madrid (B2017/BM D-3884), and Worldwide Cancer Research (15-0278). CNIO is a Severo Ochoa Cen ter of Excellence (MINECO awards SEV-2015-0510) Sí

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b1b8ddb51da52a95cc4540479224274bTest
https://hdl.handle.net/20.500.12105/6505Test

المؤلفون: María Maroto, María Salazar-Roa, Marcos Malumbres, David Partida, Guillermo de Cárcer, Marianna Trakala, Paulina Wachowicz

المساهمون: Fundación La Caixa, Ministerio de Economia y Competitividad (MINECO), Comunidad de Madrid, Worldwide Cancer Research (WCR), European Union (EU), Consolider-Ingenio Programme, Ministerio de Economía y Competitividad (España), Comunidad de Madrid (España), Worldwide Cancer Research, Unión Europea

المصدر: Repisalud
Instituto de Salud Carlos III (ISCIII)

مصطلحات موضوعية: Immunology, Fluorescent Antibody Technique, POLYPLOIDIZATION, Cell Cycle Proteins, PHASE-2 TRIAL, Protein Serine-Threonine Kinases, Biology, Bioinformatics, Biochemistry, PLK1, Spindle pole body, Mice, Megakaryocyte, Proto-Oncogene Proteins, medicine, VOLASERTIB BI 6727, CELL-CYCLE, Animals, Mitosis, MEGAKARYOCYTE ENDOMITOSIS, IN-VIVO, Mice, Knockout, AURORA-B, Cell Differentiation, POLO-LIKE KINASES, INHIBITOR VOLASERTIB, Cell Biology, Hematology, Cell cycle, Flow Cytometry, Protein-Serine-Threonine Kinases, Thrombocytopenia, Cell biology, Spindle checkpoint, medicine.anatomical_structure, Centrosome, MITOSIS, M Phase Cell Cycle Checkpoints, Endomitotic cell cycle, Megakaryocytes

الوصف: Polyploidization in megakaryocytes is achieved by endomitosis, a specialized cell cycle in which DNA replication is followed by aberrant mitosis. Typical mitotic regulators such as Aurora kinases or Cdk1 are dispensable for megakaryocyte maturation, and inhibition of mitotic kinases may in fact promote megakaryocyte maturation. However, we show here that Polo-like kinase 1 (Plk1) is required for endomitosis, and ablation of the Plk1 gene in megakaryocytes results in defective polyploidization accompanied by mitotic arrest and cell death. Lack of Plk1 results in defective centrosome maturation and aberrant spindle pole formation, thus impairing the formation of multiple poles typically found in megakaryocytes. In these conditions, megakaryocytes arrest for a long time in mitosis and frequently die. Mitotic arrest in wild-type megakaryocytes treated with Plk1 inhibitors or Plk1-null cells is triggered by the spindle assembly checkpoint (SAC), and can be rescued in the presence of SAC inhibitors. These data suggest that, despite the dispensability of proper chromosome segregation in megakaryocytes, an endomitotic SAC is activated in these cells upon Plk1 inhibition. SAC activation results in defective maturation of megakaryocytes and cell death, thus raising a note of caution in the use of Plk1 inhibitors in therapeutic strategies based on polyploidization regulators. This work was supported by a fellowship from the Foundation La Caixa (M.T.), and the Cell Division and Cancer group of the CNIO was funded by the Ministry of Economy and Competitiveness (SAF2012-38215), Consolider-Ingenio 2010 Programme (SAF2014-57791-REDC), Red Tematica CellSYS (BFU2014-52125-REDT), Comunidad de Madrid (OncoCycle Programme, S2010/BMD-2470), Worldwide Cancer Research (WCR #15-0278), and the MitoSys project (HEALTH-F5-2010-241548, European Union Seventh Framework Programme). Sí

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::558ebef83a0c23c67396b456765a853eTest
https://doi.org/10.1182/blood-2015-03-634402Test

المؤلفون: Eusebio Manchado, David Shields, María Sanz-Flores, David Partida, Marcos Malumbres, H. Raza Ali, Todd VanArsdale, Elisabet Zapatero-Solana, Miguel Quintela-Fandino, Mónica Álvarez-Fernández, Belén Sanz-Castillo, Scott W. Lowe, María Salazar-Roa, Carlos Caldas

المساهمون: Malumbres, Marcos [0000-0002-0829-6315], Apollo - University of Cambridge Repository

مصطلحات موضوعية: 0301 basic medicine, Mice, Nude, Breast Neoplasms, Biology, Protein Serine-Threonine Kinases, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Mice, Breast cancer, RNA interference, Cell Line, Tumor, medicine, Animals, Humans, Protein Phosphatase 2, Kinase activity, Molecular Biology, Mitosis, Kinase, Cancer, Cell Biology, Cell cycle, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Mitotic exit, Gene Knockdown Techniques, Cancer research, Female, Microtubule-Associated Proteins

الوصف: PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit. Despite its critical role in cell cycle progression in multiple organisms, its relevance as a therapeutic target in human cancer and its dependence of PP2A activity is mostly unknown. Here we show that MASTL overexpression predicts poor survival and shows prognostic value in breast cancer patients. MASTL knockdown or knockout using RNA interference or CRISPR/Cas9 systems impairs proliferation of a subset of breast cancer cells. The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. By using a new inducible CRISPR/Cas9 system in breast cancer cells, we show that genetic ablation of MASTL displays a significant therapeutic effect in vivo. All together, these data suggest that the PP2A inhibitory kinase MASTL may have both prognostic and therapeutic value in human breast cancer.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6619ed9562a450a9b449568e929a91cTest
https://www.repository.cam.ac.uk/handle/1810/292103Test

المؤلفون: Marta Cañamero, Kumiko Samejima, Marianna Trakala, Ángel Martínez-Ramírez, William C. Earnshaw, Guillermo de Cárcer, Ignacio Pérez de Castro, David Partida, Alba de Martino, Alejandra González-Loyola, Gonzalo Fernández-Miranda, Hiromi Ogawa, Marcos Malumbres

مصطلحات موضوعية: Cyclin-Dependent Kinase Inhibitor p21, Carcinogenesis, Aurora inhibitor, Aurora B kinase, Gene Expression, Biology, Aurora kinase, Chromosome instability, Animals, Aurora Kinase B, Gene Silencing, Molecular Biology, Mitosis, Cells, Cultured, Oncogene, Kinase, Cell Biology, Articles, Cell cycle, Fibroblasts, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Aneuploidy, Cell biology, Mice, Inbred C57BL, embryonic structures, biological phenomena, cell phenomena, and immunity

الوصف: Aurora kinase B, one of the three members of the mammalian Aurora kinase family, is the catalytic component of the chromosomal passenger complex, an essential regulator of chromosome segregation in mitosis. Aurora B is overexpressed in human tumors although whether this kinase may function as an oncogene in vivo is not established. Here, we report a new mouse model in which expression of the endogenous Aurkb locus can be induced in vitro and in vivo. Overexpression of Aurora B in cultured cells induces defective chromosome segregation and aneuploidy. Long-term overexpression of Aurora B in vivo results in aneuploidy and the development of multiple spontaneous tumors in adult mice, including a high incidence of lymphomas. Overexpression of Aurora B also results in a reduced DNA damage response and decreased levels of the p53 target p21(Cip1) in vitro and in vivo, in line with an inverse correlation between Aurora B and p21(Cip1) expression in human leukemias. Thus, overexpression of Aurora B may contribute to tumor formation not only by inducing chromosomal instability but also by suppressing the function of the cell cycle inhibitor p21(Cip1).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f697fc483285424a7f4bfeacc99e968fTest
https://europepmc.org/articles/PMC4573715Test/

المؤلفون: Marta Cañamero, Manuel Eguren, Esther Rodríguez-Díez, Dolores Martinez, Pierre Dubus, David Partida, Marcos Malumbres, Marta Gómez de Cedrón, Veronika Sexl, Victor Quereda, Florian Bellutti, Michaela Prchal-Murphy, Karoline Kollmann

المصدر: Blood. 124(15)

مصطلحات موضوعية: Adoptive cell transfer, Carcinogenesis, Immunology, Fusion Proteins, bcr-abl, Biochemistry, Mice, Animals, Alleles, Cyclin, Cell Line, Transformed, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor Proteins, biology, Cell Death, Cyclin-dependent kinase 4, Kinase, Cyclin-Dependent Kinase 4, Cell Biology, Hematology, Cyclin-Dependent Kinase 6, Hematopoietic Stem Cells, Fusion protein, Cell biology, Hematopoiesis, Haematopoiesis, Gene Ontology, Cell culture, biology.protein, Mutant Proteins, Cyclin-dependent kinase 6

الوصف: Cdk4 and Cdk6 are related protein kinases that bind d-type cyclins and regulate cell-cycle progression. Cdk4/6 inhibitors are currently being used in advanced clinical trials and show great promise against many types of tumors. Cdk4 and Cdk6 are inhibited by INK4 proteins, which exert tumor-suppressing functions. To test the significance of this inhibitory mechanism, we generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6(R/R) mice display altered development of the hematopoietic system without enhanced tumor susceptibility, either in the presence or absence of p53. Unexpectedly, Cdk6 R31C impairs the potential of hematopoietic progenitors to repopulate upon adoptive transfer or after 5-fluorouracil-induced damage. The defects are overcome by eliminating sensitivity of cells to INK4 inhibitors by introducing the INK4-insensitive Cdk4 R24C allele, and INK4-resistant mice are more susceptible to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, Cdk6 R31C causes increased binding of p16(INK4a) to wild-type Cdk4, whereas cells harboring Cdk4 R24C and Cdk6 R31C are fully insensitive to INK4 inhibitors, resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in hematopoietic tumor development and suggest a role for Cdk6 in sequestering INK4 proteins away from Cdk4.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8d3221fbc40880fd18ad59a91c4e5af8Test
https://pubmed.ncbi.nlm.nih.gov/25157181Test

المؤلفون: Raúl Méndez, Ramón Campos-Olivas, Rosa Pascual, Eduardo Rial, Katherine Allen, María Salazar-Roa, Patricia Boya, David Partida, Asish K. Saha, Carolina Maestre, Manuel Pérez, Lorena Esteban-Martínez, Marcos Malumbres, Miguel López, Elena Doménech, Gonzalo Fernández-Miranda, Esther Seco, Diego Megías, Guillermo Velasco

المصدر: Nature cell biology. 17(10)

مصطلحات موضوعية: Programmed cell death, Paclitaxel, Cdc20 Proteins, Cell Survival, Phosphofructokinase-2, Blotting, Western, Mice, Nude, Antineoplastic Agents, Apoptosis, Oxidative phosphorylation, Mitochondrion, AMP-Activated Protein Kinases, AMP-activated protein kinase, Cell Line, Tumor, Mitophagy, Autophagy, Animals, Humans, Mitosis, Cells, Cultured, Mice, Knockout, Microscopy, Confocal, biology, AMPK, Cell Biology, Fibroblasts, Embryo, Mammalian, Xenograft Model Antitumor Assays, Cell biology, biology.protein, MCF-7 Cells, M Phase Cell Cycle Checkpoints, Female, RNA Interference, Glycolysis

الوصف: Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1654ac316a5d520f5d10228832fb60aaTest
https://pubmed.ncbi.nlm.nih.gov/26322680Test

المؤلفون: Daniel K. Nomura, Ku-Lung Hsu, Sherry Niessen, Paul E. O'Brien, Weiwei Li, David Partida, Enrique Saez, Joanna Pawlak, Jason R. Thomas, Matthew J. Watt, C. Godio, Jae Won Chang, Eduardo Domínguez, Aaron P. Russell, Benjamin F. Cravatt, Andrea Galmozzi

المصدر: Nature chemical biology

مصطلحات موضوعية: Proteomics, Phenotypic screening, Protein Array Analysis, Biology, Article, Small Molecule Libraries, Diabetes mellitus genetics, Mice, Drug Delivery Systems, Drug Discovery, Diabetes Mellitus, Animals, Obesity, Carboxylesterase 3, Molecular Biology, Cells, Cultured, Genetics, Drug discovery, Cell Biology, Phenotype, Disease Models, Animal, Carboxylic Ester Hydrolases

الوصف: Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means are often required to determine the biologically relevant target (or targets) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3, also known as Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is markedly elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1b0b3eedc6dd280f6a21462767c62068Test
https://pubmed.ncbi.nlm.nih.gov/24481303Test

المؤلفون: David Partida, Enrique Saez, Wen-Ling Chou, Kevin Kwan, Hui Yeung, Andrew I. Su, Andrea Galmozzi

المصدر: PLoS ONE, Vol 8, Iss 8, p e72511 (2013)
PLoS ONE

مصطلحات موضوعية: Cellular differentiation, Gene Expression, Peroxisome proliferator-activated receptor, Adipose tissue, lcsh:Medicine, Cell Fate Determination, Mice, chemistry.chemical_compound, Adipose Tissue, Brown, Adipocyte, Molecular Cell Biology, Brown adipose tissue, Adipocytes, Regulatory Elements, Transcriptional, lcsh:Science, Conserved Sequence, chemistry.chemical_classification, Regulation of gene expression, Genetics, Adipogenesis, Multidisciplinary, Stem Cells, Cell Differentiation, Cell biology, medicine.anatomical_structure, Organ Specificity, Regulatory sequence, Medicine, Research Article, Signal Transduction, Transcriptional Activation, Adipose Tissue, White, Mice, Transgenic, Biology, Molecular Genetics, medicine, Animals, Gene Regulation, Obesity, Nutrition, Gene Expression Profiling, lcsh:R, Computational Biology, PPAR gamma, Gene Expression Regulation, chemistry, Genetic Loci, lcsh:Q, Nuclear Receptor Signaling, Developmental Biology

الوصف: Adipose tissue renewal and obesity-driven expansion of fat cell number are dependent on proliferation and differentiation of adipose progenitors that reside in the vasculature that develops in coordination with adipose depots. The transcriptional events that regulate commitment of progenitors to the adipose lineage are poorly understood. Because expression of the nuclear receptor PPARγ defines the adipose lineage, isolation of elements that control PPARγ expression in adipose precursors may lead to discovery of transcriptional regulators of early adipocyte determination. Here, we describe the identification and validation in transgenic mice of 5 highly conserved non-coding sequences from the PPARγ locus that can drive expression of a reporter gene in a manner that recapitulates the tissue-specific pattern of PPARγ expression. Surprisingly, these 5 elements appear to control PPARγ expression in adipocyte precursors that are associated with the vasculature of adipose depots, but not in mature adipocytes. Characterization of these five PPARγ regulatory sequences may enable isolation of the transcription factors that bind these cis elements and provide insight into the molecular regulation of adipose tissue expansion in normal and pathological states.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bfd549e0b4689801c2acd7a24b207f85Test
http://europepmc.org/articles/PMC3757023?pdf=renderTest