Direct regulation of BCL-2 by FLI-1 is involved in the survival of FLI-1-transformed erythroblasts.
Rearrangement of the FLI-1 locus with ensuing overexpression of FLI-1 is an early event in Friend murine leukemia virus-induced disease. When overexpressed in primary erythroblasts, FLI-1 blocks erythropoeitin (Epo)-induced terminal differentiation and inhibits apoptosis normally induced in response to Epo withdrawal. We show here that the survival-inducing property of FLI-1 is associated with increased transcription of BCL-2. We further show that FLI-1 binds BCL-2 promoter sequences in transformed erythroblasts, and in vitro studies identify specific FLI-1-binding sites essential for the transactivation of the BCL-2 promoter by FLI-1. Analysis of FLI-1 mutants showed a correlation between the ability of FLI-1 to transactivate BCL-2 promoter sequences and their ability to inhibit apoptosis in the absence of Epo. Moreover, inhibitor studies confirmed the essential role of BCL-2 for FLI-1-transformed erythroblast survival. Finally, enforced expression of BCL-2 was sufficient to promote survival and terminal differentiation of erythroblasts in the absence of Epo. These results show that BCL-2 is an in vivo target of FLI-1 in FLI-1-transformed erythroblasts and that its deregulated expression is instrumental in the survival of these cells.
Lesault
Isabelle
I
CNRS UMR146, Institut Curie-Section de Recherche, Centre Universitaire, Bat. 110, 91405 Orsay, France.
Quang
Christine Tran
CT
Frampton
Jon
J
Ghysdael
Jacques
J
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology*; D002645:Chickens; D018076:DNA, Complementary; D024202:Electrophoretic Mobility Shift Assay; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D019254:Genes, bcl-2; D051379:Mice; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011784:Quail; D015854:Up-Regulation / Q000502:physiology*
D018076:DNA, Complementary; D004921:Erythropoietin