RESUMO
BACKGROUND: Myogenesis is a highly regulated process ending with the formation of myotubes, the precursors of skeletal muscle fibers. Differentiation of myoblasts into myotubes is controlled by myogenic regulatory factors (MRFs) that act as terminal effectors of signaling cascades involved in the temporal and spatial regulation of muscle development. Such signaling cascades converge and are controlled at the level of intracellular trafficking, but the mechanisms by which myogenesis is regulated by the endosomal machinery and trafficking is largely unexplored. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery composed of four complexes ESCRT-0 to ESCRT-III regulates the biogenesis and trafficking of endosomes as well as the associated signaling and degradation pathways. Here, we investigate its role in regulating myogenesis. RESULTS: We uncovered a new function of the ESCRT-0 hepatocyte growth factor-regulated tyrosine kinase substrate Hrs/Hgs component in the regulation of myogenesis. Hrs depletion strongly impairs the differentiation of murine and human myoblasts. In the C2C12 murine myogenic cell line, inhibition of differentiation was attributed to impaired MRF in the early steps of differentiation. This alteration is associated with an upregulation of the MEK/ERK signaling pathway and a downregulation of the Akt2 signaling both leading to the inhibition of differentiation. The myogenic repressors FOXO1 as well as GSK3ß were also found to be both activated when Hrs was absent. Inhibition of the MEK/ERK pathway or of GSK3ß by the U0126 or azakenpaullone compounds respectively significantly restores the impaired differentiation observed in Hrs-depleted cells. In addition, functional autophagy that is required for myogenesis was also found to be strongly inhibited. CONCLUSIONS: We show for the first time that Hrs/Hgs is a master regulator that modulates myogenesis at different levels through the control of trafficking, signaling, and degradation pathways.
Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte , Desenvolvimento Muscular , Animais , Diferenciação Celular , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno , Transdução de SinaisRESUMO
MAIN OBJECTIVE: determine the profile of the hormonal receptors and HER2 in order to optimize the patient's treatment by hormonotherapy and to propose targeted therapeutic to the few patients can procure themselves, when the indication is put. SECONDARY OBJECTIVES: show the feasibility of these exams in sub-Saharan Africa and also the necessity to improve the technical tray permitting to do these exams in routine thus. PATIENTS AND METHODS: Preliminary results of a prospective, descriptive study, on 10 months, achieved to the Cancerology service of Treichville CHU in Abidjan (Ivory Coast). Our results were about 22 patients. RESULTS: The middle age of our patients was of 42.7 years. The stages to the diagnosis were advanced (86%) with nodes metastasis (77%), 8 patients out of 20 were RH+ of which only one postmenopausal patient, 8 patients out of 20 were HER2+ of which 2 to 2++ and 6 to 3+++. The FISH test has been achieved for the 2 positive patients to 2 ++ by IHC and came back positive. One of patients HER2+ could have adjuvant Herceptin. CONCLUSION: Breast cancer is bad prognosis affection in our developing countries because of the patient's young age, of the advanced stages to the diagnosis. The knowledge of the status of the hormonal receptors and the HER2 over expression is necessary, as well the importance to pursue this survey and to set up an immunohistochemy unit in Ivory Coast. It will permit the realization in routine of these exams and, then, the improvement of the breast cancer patient's treatment.
