RESUMEN
Polycomb group (PcG) proteins assemble to form large multiprotein complexes involved in gene silencing. Evidence suggests that PcG complexes are heterogeneous with respect to both protein composition and specific function. MPc3 is a recently described mouse Polycomb (Pc) protein that shares structural homology with at least two other Pc proteins, M33 and MPc2. All three Pc proteins bind another PcG protein, RING1, through a conserved carboxy-terminal C-box motif. Here, data are presented demonstrating that MPc3 also interacts with AF9, a transcriptional activator implicated in the development of acute leukemias. The carboxy-terminus of AF9 is fused to the MLL protein in leukemias characterized by t(9;11)(p22;q23) chromosomal translocations. Importantly, it is the carboxy-terminus of AF9 to which MPc3 binds. The AF9 binding site of MPc3 maps to a central, non-conserved, region of the polypeptide sequence. In contrast to MPc3, data indicate that the Pc protein M33 does not interact with AF9. This finding suggests a potentially unique role for MPc3 in linking a PcG silencing complex to a transcriptional activator protein.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 9 , Proteínas de Unión al ADN/metabolismo , Leucemia Bifenotípica Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proto-Oncogenes , Proteínas Represoras/metabolismo , Transactivadores/metabolismo , Factores de Transcripción , Translocación Genética , Células 3T3 , Animales , Sitios de Unión , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Ratones , Proteínas de Transporte de Membrana Mitocondrial , Proteína de la Leucemia Mieloide-Linfoide , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Complejo Represivo Polycomb 1 , Proteínas del Grupo Polycomb , Pruebas de Precipitina , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/genética , Saccharomyces cerevisiae , Transactivadores/genética , Técnicas del Sistema de Dos HíbridosRESUMEN
The MLL gene is involved in translocations associated with both acute lymphoblastic and acute myelogenous leukemia. These translocations fuse MLL with one of over 30 partner genes. Collectively, the MLL partner genes do not share a common structural motif or biochemical function. We have identified a protein interaction between the two most common MLL fusion partners AF4 and AF9. This interaction is restricted to discrete nuclear foci we have named 'AF4 bodies'. The AF4 body is non-nucleolar and is not coincident with any known nuclear structures we have examined. The AF4-AF9 interaction is maintained by the MLL-AF4 fusion protein, and expression of the MLL-AF4 fusion can alter the subnuclear localization of AF9. In view of other research indicating that other MLL fusion partners also interact with one another, these results suggest that MLL fusion partners may participate in a web of protein interactions with a common functional goal. The disruption of this web of interactions by fusion with MLL may be important to leukemogenesis.