The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis

Oikawa, Tsuneyuki; Yamada, Toshiyuki; Kihara-Negishi, Fumiko; Yamamoto, Hiroaki; Kondoh, Nobuo; Hitomi, Yoshiaki; Hashimoto, Yuichi

doi:10.1038/sj.cdd.4400534

Cited by 97 publications

(60 citation statements)

References 145 publications

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“…It has been established that DMSO treatment results in Spi-1/PU.1 downregulation, which in turn is required for terminal erythroid differentiation (Schuetze et al, 1992). Consistently, enforced expression of Spi-1/PU.1 blocks cell differentiation (Rao et al, 1997;Yamada et al, 1997;Oikawa et al, 1999). Similarly, overexpression of Fli-1 inhibits chemically induced terminal differentiation of MEL cells (Starck et al, 1999;Tamir et al, 1999).…”

Section: Introductionmentioning

confidence: 79%

Spi-1/PU.1 but not Fli-1 inhibits erythroid-specific alternative splicing of 4.1R pre-mRNA in murine erythroleukemia cells

Théoleyre

Deguillien²,

Morinière³

et al. 2003

Oncogene

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The inclusion of exon 16 in mature protein 4.1R mRNA arises from a stage-specific splicing event that occurs during late erythroid development. We have shown that mouse erythroleukemia (MEL) cells reproduce this erythroid-specific splicing event upon induction of differentiation. We here found that this splicing event is regulated specifically in erythroleukemic cells that have the potential to differentiate and produce hemoglobin, regardless of the nature of the differentiation inducer. Knowing that dysregulated expression of spi-1/pu.1 and fli-1 oncogenes is involved in MEL cell differentiation arrest, we looked at their effect on exon 16 erythroid splicing. We found that exon 16 inclusion requires Spi-1/ PU.1 shutdown in MEL cells, and that enforced expression of Spi-1/PU.1 inhibits exon selection, regardless of the presence or absence of a chemical inducer. By contrast, endogenous overexpression or enforced expression of Fli-1 has no effect on exon selection. We further showed that Spi-1/PU.1 acts similarly on the endogenous and on a transfected exon 16, suggesting a promoterindependent effect of Spi-1/PU.1 on splicing regulation. This study provides the first evidence that Spi-1/PU.1 displays the unique property, not shared with Fli-1, to inhibit erythroid-specific pre-mRNA splicing in erythroleukemia cell context.

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Section: Introductionmentioning

confidence: 79%

Spi-1/PU.1 but not Fli-1 inhibits erythroid-specific alternative splicing of 4.1R pre-mRNA in murine erythroleukemia cells

Théoleyre

Deguillien²,

Morinière³

et al. 2003

Oncogene

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“…In normal hematopoiesis, the expression of PU.1 is upregulated in B cells and myelomonocytic lineages, but downregulated in T cells and erythroid cells. PU.1 encodes a transcription factor that belongs to the Ets family and controls the expression of many Bcell-and macrophage-specific genes, including the immunoglobulin genes and the macrophage colony stimulation factor receptor (M-CSFR) gene (MoreauGachelin, 1994;Tenen et al, 1997;Oikawa et al, 1999). Furthermore, sustained expression of PU.1 in erythroblasts is believed to contribute to the blocking of erythroid differentiation, as we and others have reported (Rao et al, 1997;Yamada et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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“…Its activity is likely mediated through its transcriptional activator function and involves a large set of target genes and interacting proteins (for review see Oikawa et al, 1999). Spi-1/PU.1 is not involved in the development of the erythroid cell lineage since erythropoiesis occurs normally in spi-1/PU.1 de®cient mice (McKercher et al, 1996;Scott et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts

et al. 2001

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Activation of the spi-1/PU.1 proto-oncogene and loss of p53 function are genetic alterations associated with the emergence of Friend malignant erythroleukemic cells. To address the role of p53 during erythroleukemogenesis, spi-1 transgenic mice (spi-1-Tg) which develop erythroleukemia were bred with p53-de®cient mice. Three classes of spi-1 transgenic mice di ering in their p53 functional status (p53 +/+ , p53 +/7 and p53 7/7 ) were generated. These mice developed a unique pattern of erythroleukemia. In wild-type p53 spi-1-Tg mice, none of the primary erythroleukemic spleen cells displayed autonomous growth in vitro and in vivo. In contrast, in p53 +/7 spi-1-Tg mice, erythroleukemic cells gave rise to growth factor-independent cell lines and generated tumors in vivo. Malignancy was associated with loss of the wild-type p53 allele. The p53 7/7 spi-1-Tg mice developed erythroleukemia with a total incidence and a reduced latency compared to the two other genotypes. Unexpectedly, 50% of p53 7/7 spi-1-Tg erythroleukemic spleens generated cell lines that were strictly dependent upon erythropoietin (Epo) for proliferation, whereas the remainder proliferated independently of cytokines. Moreover, only 70% of these spleen cells were tumorigenic. These ®ndings indicate that p53 germ-line deletion did not confer malignancy to spi-1-transgenic proerythroblasts. Moreover Epo independence and tumorigenicity appear as separable phenotypic characteristics revealing that the spi-1-Tg proerythroblasts progress towards malignancy through multiple oncogenic events. Oncogene (2001) 20, 5484 ± 5492.

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The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis

Abstract: The PU

Cited by 97 publications

References 145 publications

Spi-1/PU.1 but not Fli-1 inhibits erythroid-specific alternative splicing of 4.1R pre-mRNA in murine erythroleukemia cells

Spi-1/PU.1 but not Fli-1 inhibits erythroid-specific alternative splicing of 4.1R pre-mRNA in murine erythroleukemia cells

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts

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