RESUMEN
p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(-) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(-) or latency I EBV(+) cells, whereas latency III EBV(+) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(-) or latency I EBV(+) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV(+) cells. p21(WAF1) which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21(WAF1) restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21(WAF1)-mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.
Asunto(s)
Apoptosis/efectos de los fármacos , Linfoma de Burkitt/tratamiento farmacológico , Herpesvirus Humano 4/aislamiento & purificación , Imidazoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/fisiología , Linfoma de Burkitt/patología , Linfoma de Burkitt/virología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/fisiología , Resistencia a Antineoplásicos , Etopósido/farmacología , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
Bax is a pro-apoptotic member of the Bcl-2 family proteins involved in the release of apoptogenic factors from mitochondria to the cytosol. Recently, it has been shown both in mammals and yeast that Bax insertion in the mitochondrial outer membrane involves at least two distinct mechanisms, one of which uses the TOM complex. Here, we show that in Drosophila, heterozygous loss of function mutations of Tom22 or Tom70, two receptors of the TOM complex, attenuates bax-induced phenotypes in vivo. These results argue that the TOM complex may be used as a mitochondrial Bax receptor in Drosophila.
