title: GATA-1 and Gfi-1B interplay to regulate Bcl-xL transcription.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Taiwan University, College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Yuan-Yeh
authors.initials: YY
authors.lastname: Kuo
authors.forename: Zee-Fen
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000494:pharmacology; D001549:Benzamides; D001665:Binding Sites; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D008156:Luciferases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051020:bcl-X Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001549:Benzamides; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C111977:GFI1B protein, human; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D012097:Repressor Proteins; D051020:bcl-X Protein; D000068877:Imatinib Mesylate; D008156:Luciferases; D016044:Fusion Proteins, bcr-abl; D001151:Arsenic