Differential Role of Insulin Receptor Substrate (IRS)-1 and IRS-2 in L6 Skeletal Muscle Cells Expressing the Arg1152 → Gln Insulin Receptor *

In L6 muscle cells expressing the Arg1152 --> Gln insulin receptor (Mut), basal tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was increased by 35% compared with wild-type cells (WT). Upon exposure to insulin, IRS-1 phosphorylation increased by 12-fold in both the Mut and WT cells. IRS-2 was constitutively phosphorylated in Mut cells and not further phosphorylated by insulin. The maximal phosphorylation of IRS-2 in basal Mut cells was paralleled by a 4-fold increased binding of the kinase regulatory loop binding domain of IRS-2 to the Arg1152 --> Gln receptor. Grb2 and phosphatidylinositol 3-kinase association to IRS-1 and IRS-2 reflected the phosphorylation levels of the two IRSs. Mitogen-activated protein kinase activation and [3H]thymidine incorporation closely correlated with IRS-1 phosphorylation in Mut and WT cells, while glycogen synthesis and synthase activity correlated with IRS-2 phosphorylation. The Arg1152 --> Gln mutant did not signal Shc phosphorylation or Shc-Grb2 association in intact L6 cells, while binding Shc in a yeast two-hybrid system and phosphorylating Shc in vitro. Thus, IRS-2 appears to mediate insulin regulation of glucose storage in Mut cells, while insulin-stimulated mitogenesis correlates with the activation of the IRS-1/mitogen-activated protein kinase pathway in these cells. IRS-1 and Shc-mediated mitogenesis may be redundant in muscle cells

3D strain map of axially loaded mouse tibia: a numerical analysis validated by experimental measurements

A combined experimental/numerical study was performed to calculate the zone of highest strain in a rat tibia loaded axially. This study is motivated by the fact that the bone remodeling analysis in this in vivo rat model should be performed at the zone of highest mechanical stimulus to maximize the measured effects. Accordingly, it is proposed that quantification of bone remodeling should be performed at the tibial crest and at the distal diaphysis. The numerical model could also be used to furnish a more subtle analysis as a precise correlation between local strain and local biological response can be obtained with the experimentally validated numerical model

Modélisation du stimulus mécanique appliqué in vivo sur un tibia de souris

L'os est constamment remodelé et s'adapte en particulier afin d'optimiser sa structure aux sollicitations mécaniques. Il semble de plus en plus évident que les cellules osseuses de type osteocytes sont utilisées par le corps comme capteur du stimulus mécanique qui est ensuite traduit en réponse biologique. Cependant, on connait beaucoup moins bien le processus par lequel les cellules "sentent" le stimulus mécanique pour le traduire en réponse biologique, phénomène appelé "mecanotransduction". Un des projets développé au Laboratoire de Biomécanique en Orthopédie consiste, en combinant des approches biomécaniques et l'utilisation de souris transgéniques, à identifier des cascades moléculaires responsables de la mécanotransduction

3D strain map of axially loaded mouse tibia: a numerical analysis validated by experimental measurements

A combined experimental/numerical study was performed to calculate the 3D octahedral shear strain map in a mouse tibia loaded axially. This study is motivated by the fact that the bone remodelling analysis, in this in vivo mouse model should be performed at the zone of highest mechanical stimulus to maximise the measured effects. Accordingly, it is proposed that quantification of bone remodelling should be performed at the tibial crest and at the distal diaphysis. The numerical model could also be used to furnish a more subtle analysis as a precise correlation between local strain and local biological response can be obtained with the experimentally validated numerical model

An Induced Ets Repressor Complex Regulates Growth Arrest during Terminal Macrophage Differentiation

Defining the molecular mechanisms that coordinately regulate proliferation and differentiation is a central issue in development. Here, we describe a mechanism in which induction of the Ets repressor METS/PE1 links terminal differentiation to cell cycle arrest. Using macrophages as a model, we provide evidence that METS/PE1 blocks Ras-dependent proliferation without inhibiting Ras-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Antiproliferative effects of METS require its interaction with DP103, a DEAD box-containing protein that assembles a novel corepressor complex. Functional interactions between the METS/DP103 complex and E2F/ pRB family proteins are also necessary for inhibition of cellular proliferation, suggesting a combinatorial code that directs permanent cell cycle exit during terminal differentiation