IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
b-catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors.
Autor/es:
GRUMOLATO L; LIU G; HAREMAKI T; MUNGAMURI S; AKIRI G; LOPEZ BERGAMI, P.; WEINSTEIN D; AARONSON S
Lugar:
Egmond aan Zee
Reunión:
Congreso; EMBO Meeting - 30 Years of Wnt Signalling; 2012
Institución organizadora:
EMBO - European Molecular Biology Organization
Resumen:
Upon Wnt signaling activation, stabilized b-catenin binds to the TCF/LEF family of transcription factors to regulate the expression of Wnt target genes. In the absence of b-catenin binding, the TCF/LEF proteins are believed to act as transcriptional repressors. Using a lentiviral TCF/LEF reporter, we identified hematopoietic tumor cells showing TCF/LEF transcriptional activation without detectable levels of stabilized b-catenin. Of note, expression of a dominant-negative TCF4 (DN-TCF4) in these cells abolished TCF/LEF activity, while shRNA-mediated down-regulation of b-catenin had no effect. DN-TCF4 also inhibited the expression of Wnt target genes, including LEF1 and axin2, as well as cell proliferation. Using both in vitro and in vivo models, we showed that TCF1 and LEF1, but not TCF4, are able to act as transcriptional activators by a mechanism independent of b-catenin. We demonstrated that TCF1 interacts instead with the transcription factor ATF2 and that the three members of the ATF2 family can synergize with TCF1 and LEF1 to stimulate TCF/LEF reporter activity. Consistent with these results, down-regulation of ATF2 and ATF7 in lymphoma cells reduced both TCF/LEF activity and axin2 expression and inhibited cell proliferation. Together, our findings indicate that activation of TCF/LEF proteins through a b-catenin-independent mechanism provides an alternative mechanism for triggering the expression of Wnt target genes and promoting growth of some hematopoietic malignancies.