Rôle de la kinase p38 dans l'apoptose induite par le cisplatine

Abstract

La transformation oncogénique conduit souvent à une augmentation de la sensibilité des cellules à l'apoptose, ce qui explique que le développement d'un cancer peut nécessiter l'acquisition d'une résistance à l'apoptose. Ce mémoire porte sur le sentier d'apoptose induit par l'agent anticancéreux cisplatine dans des cellules Rat-1 transformées par l'oncogène c-myc. Un traitement au cisplatine active la MAP kinase p38 et provoque une translocation de la protéine proapoptotique Bax à la mitochondrie, une sortie du cytochrome c au cytoplasme et la fragmentation des noyaux, tout cela d'une façon dépendante de c-myc. La MAP kinase p38 est essentielle à ces manifestations apoptotiques. Son inhibition bloque la translocation de Bax et du cytochrome c, ainsi que la fragmentation nucléaire. Les protéines ASK1 et MKK3/6, des kinases connues pour activer p38, sont activées en réponse au cisplatine de façon dépendante de c-myc, suggérant un rôle de ces protéines dans le sentier activé en réponse au cisplatine menant à l'activation de p38 et de Bax, et à la fragmentation nucléaire.

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Oncogenic transformation often leads to an increase in the sensitivity of cells to apoptosis, which explains why the development of cancer may require the acquisition of resistance to apoptosis. This dissertation focuses on the apoptosis pathway induced by the anticancer agent cisplatin in Rat-1 cells transformed by the c-myc oncogene. Cisplatin treatment activates p38 MAP kinase and causes translocation of the proapoptotic protein Bax to the mitochondrion, cytochrome c efflux to the cytoplasm, and fragmentation of nuclei, all in a c-myc-dependent manner. The p38 MAP kinase is essential for these apoptotic manifestations. Its inhibition blocks Bax and cytochrome c translocation, as well as nuclear fragmentation. The ASK1 and MKK3/6 proteins, kinases known to activate p38, are activated in response to cisplatin in a c-myc-dependent manner, suggesting a role for these proteins in the cisplatin-activated pathway leading to p38 activation. and Bax, and nuclear fragmentation.