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- Contrôle de la croissance cellulaire par les nutriments -
Réponses affichées : 13
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Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation
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PRADELLI LA, BENETEAU M, CHAUVIN C, JACQUIN MA, MARCHETTI S, MUNOZ-PINEDO C, AUBERGER P, PENDE M, RICCI JE
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2010 - Oncogene 29(11):1641-52 |
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Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.Oncogene advance online publication, 7 December 2009; doi:10.1038/onc.2009.448.
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Unité(s) :
U845 (MP)
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Rictor is a novel target of p70 S6 kinase-1
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TREINS C, WARNE PH, MAGNUSON MA, PENDE M, DOWNWARD J
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2010 - Oncogene 29(7):1003-16 |
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The rapamycin-insensitive companion of mammalian target of rapamycin (mTOR) (Rictor) is a key member of mTOR complex-2 (mTORC2), which phosphorylates the AGC kinases Akt/PKB, PKC and SGK1 at a C-terminal hydrophobic motif. We identified several novel sites on Rictor that are phosphorylated, including Thr1135, which is conserved across all vertebrates. Phosphorylation of this site on Rictor is stimulated by amino acids and growth factors through a rapamycin-sensitive signaling cascade. We demonstrate here that Rictor is a direct target of the ribosomal protein S6 kinase-1 (S6K1). Rictor phosphorylation at Thr1135 does not lead to major changes in mTORC2-kinase activity. However, phosphorylation of this site turns over rapidly and mediates 14-3-3 binding to Rictor and mTORC2, providing possibility for altered interactions of the complex. These findings reveal an unexpected signaling input into mTORC2, which is regulated by amino acids, growth factors and rapamycin.
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Unité(s) :
U845 (MP)
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eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development
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MALTA-VACAS J, CHAUVIN C, GONCALVES L, NAZARE A, CARVALHO C, MONTEIRO C, BAGREL D, JEAN-JEAN O, BRITO M
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2009 - Oncol Rep 21(6):1551-8 |
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It is now widely recognized that translation factors are involved in cancer development and that components of the translation machinery that are deregulated in cancer cells may become targets for cancer therapy. The eukaryotic Release Factor 3 (eRF3) is a GTPase that associates with eRF1 in a complex that mediates translation termination. eRF3a/GSPT1 first exon contains a (GGC)n expansion coding for proteins with different N-terminal extremities. Herein we show that the longer allele (12-GGC) is present in 5.1% (7/137) of the breast cancer patients analysed and is absent in the control population (0/135), corresponding to an increased risk for cancer development, as revealed by Odds Ratio analysis. mRNA quantification suggests that patients with the 12-GGC allele overexpress eRF3a/GSPT1 in tumor tissues relative to the normal adjacent tissues. However, using an in vivo assay for translation termination in HEK293 cells, we do not detect any difference in the activity of the eRF3a proteins encoded by the various eRF3a/GSPT1 alleles. Although the connection between the presence of eRF3a/GSPT1 12-GGC allele and tumorigenesis is still unknown, our data suggest that the presence of the 12-GGC allele provides a potential novel risk marker for various types of cancer.
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Unité(s) :
U845 (MP)
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Important role for AMPK{alpha}1 in limiting skeletal muscle cell hypertrophy
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MOUNIER R, LANTIER L, LECLERC J, SOTIROPOULOS A, PENDE M, DAEGELEN D, SAKAMOTO K, FORETZ M, VIOLLET B
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2009 - FASEB J 23(7):2264-2273 |
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Activation of AMP-activated protein kinase (AMPK) inhibits protein synthesis through the suppression of the mammalian target of rapamycin complex 1 (mTORC1), a critical regulator of muscle growth. The purpose of this investigation was to determine the role of the AMPKalpha1 catalytic subunit on muscle cell size control and adaptation to muscle hypertrophy. We found that AMPKalpha1(-/-) primary cultured myotubes and myofibers exhibit larger cell size compared with control cells in response to chronic Akt activation. We next subjected the plantaris muscle of AMPKalpha1(-/-) and control mice to mechanical overloading to induce muscle hypertrophy. We observed significant elevations of AMPKalpha1 activity in the control muscle at days 7 and 21 after the overload. Overloading-induced muscle hypertrophy was significantly accelerated in AMPKalpha1(-/-) mice than in control mice [+32 vs. +53% at day 7 and +57 vs. +76% at day 21 in control vs. AMPKalpha1(-/-) mice, respectively]. This enhanced growth of AMPKalpha1-deficient muscle was accompanied by increased phosphorylation of mTOR signaling downstream targets and decreased phosphorylation of eukaryotic elongation factor 2. These results demonstrate that AMPKalpha1 plays an important role in limiting skeletal muscle overgrowth during hypertrophy through inhibition of the mTOR-signaling pathway.-Mounier, R., Louise Lantier, Leclerc, J., Sotiropoulos, A., Pende, M., Daegelen, D., Sakamoto, K., Foretz, M., Viollet, B. Important role for AMPKalpha1 in limiting skeletal muscle cell hypertrophy.
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Unité(s) :
U845 (MP)
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mTOR/S6 Kinase Pathway Contributes to Astrocyte Survival during Ischemia
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PASTOR MD, GARCIA-YEBENES I, FRADEJAS N, PEREZ-ORTIZ JM, MORA-LEE S, TRANQUE P, MORO MA, PENDE M, CALVO S
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2009 - J Biol Chem 284(33):22067-78 |
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Neurons are highly dependent on astrocyte survival during brain damage. To identify genes involved in astrocyte function during ischemia, we performed mRNA differential display in astrocytes after oxygen and glucose deprivation (OGD). We detected a robust down-regulation of S6 kinase 1 (S6K1) mRNA that was accompanied by a sharp decrease in protein levels and activity. OGD-induced apoptosis was increased by the combined deletion of S6K1 and S6K2 genes, as well as by treatment with rapamycin that inhibits S6K1 activity by acting on the upstream regulator mTOR (mammalian target of rapamycin). Astrocytes lacking S6K1 and S6K2 (S6K1;S6K2(-/-)) displayed a defect in BAD phosphorylation and in the expression of the anti-apoptotic factors Bcl-2 and Bcl-xL. Furthermore reactive oxygen species were increased while translation recovery was impaired in S6K-deficient astrocytes following OGD. Rescue of either S6K1 or S6K2 expression by adenoviral infection revealed that protective functions were specifically mediated by S6K1, because this isoform selectively promoted resistance to OGD and reduction of ROS levels. Finally, "in vivo" effects of S6K suppression were analyzed in the permanent middle cerebral artery occlusion model of ischemia, in which absence of S6K expression increased mortality and infarct volume. In summary, this article uncovers a protective role for astrocyte S6K1 against brain ischemia, indicating a functional pathway that senses nutrient and oxygen levels and may be beneficial for neuronal survival.
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Unité(s) :
U845 (MP)
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Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy
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RISSON V, MAZELIN L, ROCERI M, SANCHEZ H, MONCOLLIN V, CORNELOUP C, RICHARD-BULTEAU H, VIGNAUD A, BAAS D, DEFOUR A, FREYSSENET D, TANTI JF, LE-MARCHAND-BRUSTEL Y, FERRIER B, CONJARD-DUPLANY A, ROMANINO K, BAUCHE S, HANTAI D, MUELLER M, KOZMA SC, THOMAS G, RUEGG MA, FERRY A, PENDE M, BIGARD X, KOULMANN N, SCHAEFFER L, GANGLOFF YG
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2009 - J Cell Biol 187(6):859-74 |
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Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.
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Unité(s) :
U845 (MP)
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Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation
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ALLIOUACHENE S, TUTTLE RL, BOUMARD S, LAPOINTE T, BERISSI S, GERMAIN S, JAUBERT F, TOSH D, BIRNBAUM MJ, PENDE M
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2008 - J. Clin. Invest. 118(11):3629-3638 |
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Factors that promote pancreatic beta cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate beta cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls beta cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged beta cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in beta cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.
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Unité(s) :
Anatomie Pathologique, U845 (MP)
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Akt activation protects pancreatic beta cells from AMPK-mediated death through stimulation of mTOR
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CAI Y, WANG Q, LING Z, PIPELEERS D, MCDERMOTT P, PENDE M, HEIMBERG H, VAN DE CASTEELE M
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2008 - Biochem. Pharmacol. 75(10):1981-1993 |
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Sustained activation of AMP-activated protein kinase (AMPK) induces apoptosis in several cell types. In pancreatic beta cells this occurs under glucose limitation, or in the presence of the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR). It is unknown whether Akt activation can counteract AMPK-mediated apoptosis, nor whether mTOR activation downstream of Akt mediates any survival signal in these conditions. We report that expression of a constitutively active form of Akt increases mTOR activity and prevents apoptosis upon AMPK activation. Akt-mediated survival was inhibited by rapamycin. Expression of a constitutively active form of the mTOR target ribosomal protein S6 kinase (S6K) or of translation factor eIF4E reduced apoptosis by glucose limitation, and co-expression of S6K and eIF4E protected beta cells to the same extent as active Akt. The protective effects of active Akt and S6K were associated with increased cellular protein synthesis activity. It is concluded that Akt stimulation of mTOR and subsequent activation of the targets by which mTOR affects protein translation are required and sufficient mechanisms for Akt-mediated survival of beta cells undergoing sustained AMPK activation.
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Unité(s) :
U845 (MP)
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S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover
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MIEULET V, ROCERI M, ESPEILLAC C, SOTIROPOULOS A, OHANNA M, OORSCHOT V, KLUMPERMAN J, SANDRI M, PENDE M
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2007 - Amer. J. Physiol. - Cell Physiol. 293(2):C712-C722 |
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A defect in protein turnover underlies multiple forms of cell atrophy. Since S6 kinase (S6K)-deficient cells are small and display a blunted response to nutrient and growth factor availability, we have hypothesized that mutant cell atrophy may be triggered by a change in global protein synthesis. By using mouse genetics and pharmacological inhibitors targeting the mammalian target of rapamycin (mTOR)/S6K pathway, here we evaluate the control of translational target phosphorylation and protein turnover by the mTOR/S6K pathway in skeletal muscle and liver tissues. The phosphorylation of ribosomal protein S6 (rpS6), eukaryotic initiation factor-4B (eIF4B), and eukaryotic elongation factor-2 (eEF2) is predominantly regulated by mTOR in muscle cells. Conversely, in liver, the MAPK and phosphatidylinositol 3-kinase pathways also play an important role, suggesting a tissue-specific control. S6K deletion in muscle mimics the effect of the mTOR inhibitor rapamycin on rpS6 and eIF4B phosphorylation without affecting eEF2 phosphorylation. To gain insight on the functional consequences of these modifications, methionine incorporation and polysomal distribution were assessed in muscle cells. Rates and rapamycin sensitivity of global translation initiation are not altered in S6K-deficient muscle cells. In addition, two major pathways of protein degradation, autophagy and expression of the muscle-specific atrophy-related E3 ubiquitin ligases, are not affected by S6K deletion. Our results do not support a role for global translational control in the growth defect due to S6K deletion, suggesting specific modes of growth control and translational target regulation downstream of mTOR.
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Unité(s) :
U845 (MP)
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New role for serum response factor in postnatal skeletal muscle growth and regeneration via the interleukin 4 and insulin-like growth factor 1 pathways
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CHARVET C, HOUBRON C, PARLAKIAN A, GIORDANI J, LAHOUTE C, BERTRAND A, SOTIROPOULOS A, RENOU L, SCHMITT A, MELKI J, LI Z, DAEGELEN D, TUIL D
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2006 - Mol. Cell. Biol. 26(17):6664-6674 |
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Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration.
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Unité(s) :
U810
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mTOR, Akt, S6 kinases and the control of skeletal muscle growth
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PENDE M
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2006 - Bull. Cancer 93(5):E39-E43 |
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In multicellular organisms, growth and metabolism are controlled by extracellular signals, such as insulin and insulin-like growth factors (IGFs). Depending on nutrient availability, these factors regulate cell number, cell size, storage of lipids, proteins and sugars. Here we will review recent literature on the intracellular signal transduction pathways regulating the anabolic responses in skeletal muscles. Emphasis will be put on three serine/threonine kinases, mTOR, Akt and S6 Kinase (S6K), and their role in the integration of environmental cues and the coordination of muscle growth.
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Unité(s) :
U810
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The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity
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SHAHBAZIAN D, ROUX PP, MIEULET V, COHEN MS, RAUGHT B, TAUNTON J, HERSHEY JW, BLENIS J, PENDE M, SONENBERG N
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2006 - EMBO J. 25(12):2781-2791 |
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The eukaryotic translation initiation factor 4B (eIF4B) plays a critical role in recruiting the 40S ribosomal subunit to the mRNA. In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin-sensitive manner. Here we demonstrate that the p90 ribosomal protein S6 kinase (RSK) phosphorylates eIF4B on the same residue. The relative contribution of the RSK and S6K modules to the phosphorylation of eIF4B is growth factor-dependent, and the two phosphorylation events exhibit very different kinetics. The S6K and RSK proteins are members of the AGC protein kinase family, and require PDK1 phosphorylation for activation. Consistent with this requirement, phosphorylation of eIF4B Ser422 is abrogated in PDK1 null embryonic stem cells. Phosphorylation of eIF4B on Ser422 by RSK and S6K is physiologically significant, as it increases the interaction of eIF4B with the eukaryotic translation initiation factor 3.
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Unité(s) :
U810
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Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation
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SOTIROPOULOS A, OHANNA M, KEDZIA C, MENON RK, KOPCHICK JJ, KELLY PA, PENDE M
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2006 - Proc. Nat. Acad. Sci. USA 103(19):7315-7320 |
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Growth hormone (GH) participates in the postnatal regulation of skeletal muscle growth, although the mechanism of action is unclear. Here we show that the mass of skeletal muscles lacking GH receptors is reduced because of a decrease in myofiber size with normal myofiber number. GH signaling controls the size of the differentiated myotubes in a cell-autonomous manner while having no effect on size, proliferation, and differentiation of the myoblast precursor cells. The GH hypertrophic action leads to an increased myonuclear number, indicating that GH facilitates fusion of myoblasts with nascent myotubes. NFATc2, a transcription factor regulating this phase of fusion, is required for GH action because GH is unable to induce hypertrophy of NFATc2-/- myotubes. Finally, we provide three lines of evidence suggesting that GH facilitates cell fusion independent of insulin-like growth factor 1 (IGF-1) up-regulation. First, GH does not regulate IGF-1 expression in myotubes; second, GH action is not mediated by a secreted factor in conditioned medium; third, GH and IGF-1 hypertrophic effects are additive and rely on different signaling pathways. Taken together, these data unravel a specific function of GH in the control of cell fusion, an essential process for muscle growth.
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Unité(s) :
U810
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