GATA-1 and Gfi-1B Interplay To Regulate Bcl-xL Transcription

• DOI: 10.1128/mcb.02212-06
• Publication Date: 2007-04-10T00:35:59Z
• Authors: Yuan-Yeh Kuo; Zee-Fen Chang
• Keywords: 0301 basic medicine; Chromatin Immunoprecipitation; 0303 health sciences; Binding Sites; Fusion Proteins, bcr-abl; Apoptosis; Piperazines; Arsenic; Cell Line; 3. Good health; 03 medical and health sciences; Cell Transformation, Neoplastic; Gene Expression Regulation; Genes, Reporter; Proto-Oncogene Proteins; Benzamides; Imatinib Mesylate; Humans; GATA1 Transcription Factor; K562 Cells; Luciferases; Promoter Regions, Genetic; Cell Line, Transformed; Protein Binding

The induction of Bcl-x(L) is critical for the survival of late proerythroblasts. The erythroid-specific transcriptional network that regulates Bcl-x(L) expression in erythropoiesis remains unclear. The activation of the central erythropoietic transcriptional factor, GATA-1, leads to the early, transient induction of a transcription repressor, Gfi-1B, followed by the late induction of Bcl-x(L) during erythroid maturation in G1ER cells. Chromatin immunoprecipitation assays demonstrated that a constant level of GATA-1 binds to the Bcl-x promoter throughout the entire induction period, while Gfi-1B is transiently associated with the promoter in the early phase. The sustained expression of Gfi-1B abolished GATA-1-induced Bcl-x(L) expression. Here, we present evidence that GATA-1 binds to the noncanonical GATT motif of the Bcl-x promoter for trans-activation. Gfi-1B expressed at increased levels is recruited to the Bcl-x promoter through its association with GATA-1, suppressing Bcl-x(L) transcription. Therefore, the down-regulation of Gfi-1B in the late phase of erythroid maturation is necessary for Bcl-x(L) induction. Furthermore, we show that the inhibition of Bcr-Abl kinase by treatment with imatinib caused the up-regulation of Gfi-1B in K562 cells, where Gfi-1B also cooperated with GATA-1 to repress Bcl-x(L) transcription. Gfi-1B knockdown by RNA interference diminished imatinib-induced apoptosis, while the overexpression of Gfi-1B sensitized K562 cells to arsenic-induced death. These findings illuminate the role of Gfi-1B in GATA-1-mediated transcription in the survival aspect of erythroid cells.