Structure of the human Bim gene and its transcriptional regulation in Baf-3, interleukin-3-dependent hematopoietic cells.
Deprivation of cytokines induces cell cycle arrest and apoptosis in cytokine-dependent hematopoietic progenitors. Previous studies have indicated that in Baf-3, interleukin (IL)-3-dependent cells, apoptosis is caused predominantly by Bim, a BH3-only cell death activator that belongs to the Bcl-2 superfamily. Because Bim mRNA is induced by IL-3 starvation, we hypothesized that signals originating from the IL-3 receptor might regulate the expression of Bim at the level of its transcription. Here, we identified the transcriptional initiation site and three candidate remote enhancer/silencer regions of the Bim gene. We show that the region of the gene upstream of the initiation site exhibits strong promoter activity and that there are negative regulatory regions within the first intron. However, none of these transcriptional regulatory elements was IL-3-dependent. In addition, a nuclear run-off assay revealed a similar rate of transcription initiation in the absence or presence of IL-3. Although others have demonstrated the transcriptional regulation of Bim by nerve growth factor (NGF) in neuronally differentiated PC12 pheochromocytoma cells, this is unlikely to be the mechanism through which IL-3 downregulates the expression of Bim in Baf-3 cells.
Matsui
Hirotaka
H
Department of Molecular Oncology & Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8553, Japan.
Shinjyo
Tetsuharu
T
Inaba
Toshiya
T
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D040461:Gene Components; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D020932:Nerve Growth Factor / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D037941:Silencer Elements, Transcriptional; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D007377:Interleukin-3; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020932:Nerve Growth Factor