Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta.

Sasaki, Koichi; Yagi, Hideshi; Bronson, Roderick T.; Tominaga, Kumi; Matsunashi, Tatsuro; Deguchi, Kenji; Tani, Yoshihiko; Kishimoto, Tadamitsu; Komori, Toshihisa

doi:10.1073/pnas.93.22.12359

Cited by 353 publications

(240 citation statements)

References 35 publications

(42 reference statements)

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“…The consensus DNA sequence recognized by AML1, TGT/cGGT (Meyers et al, 1993), is contained in the promoter and enhancer regions of many hematopoietic-speci®c genes . Although murine genes encoding AML2 and AML3 have been identi®ed (Levanon et al, 1994), an essential role for AML1 in hematopoiesis was demonstrated by AML1 (Okuda et al, 1996;Wang et al, 1996a) and CBFb (Niki et al, 1997;Sasaki et al, 1996;Wang et al, 1996b) knock-out experiments. Mice that lack AML1 or CBFb have absent fetal liver hematopoiesis and die between days E11.5-13.5 with a distinct pattern of central nervous system hemorrhage.…”

Section: Introductionmentioning

confidence: 99%

The t(8;21) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1

et al. 1999

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The 8;21 translocation is the most common cytogenetic abnormality in human acute myelogenous leukemia, joining the AML1 gene on chromosome 21, to the ETO gene on chromosome 8, forming the AML1/ETO fusion gene. The AML1/ETO fusion protein has been shown to function mainly as a transcriptional repressor of AML1 target genes and to block AML1 function in vitro and in vivo. However, AML1/ETO can also activate the BCL-2 promoter and cause enhanced hematopoietic progenitor self-renewal in vitro, suggesting gain-of-functions unique to the fusion protein. We used NIH3T3 cells to determine the transforming capacity of AML1/ETO, and to further characterize its mechanism of action. Expression of AML1/ETO in NIH3T3 cells caused cell-type speci®c cell death, and cellular transformation, characterized by phenotypic changes, anchorage-independent growth, and tumor formation in nude mice. In contrast, neither expression of AML1A, AML1B or ETO altered the normal growth pattern of the cells. To investigate the mechanism of transformation by AML1/ETO, we analysed the levels of activated, phosphorylated c-Jun (ser63) and other constituents of the AP-1 complex, in the presence of various AML1/ ETO related proteins. Expression of AML1/ETO increased the level of c-Jun-P (ser63), and activated AP-1 dependent transcription, which was inhibited by expression of a dominant-negative c-Jun protein. Mutational analysis revealed that the runt homology domain (RHD) and a C-terminal transcriptional repression domain in AML1/ETO are required for transformation, activation of c-Jun and increased AP-1 activity. These results establish the transforming potential of the t(8;21) fusion protein and link this gain-of-function property to modulation of AP-1 activity.

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Section: Introductionmentioning

confidence: 99%

The t(8;21) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1

et al. 1999

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“…The t(8;21) translocation generates an AML1/ETO fusion protein whereas the heterodimeric partner of AML1, CBFb, is involved in the inv(16) abnormality, which generates a CBFb-MYH11 fusion product (Liu et al, 1993). AML1 (also called CBFA2) and CBFb play essential roles in hematopoietic development; homozygous disruption of either gene in mice, using targeted homologous recombination, results in absent fetal liver hematopoiesis, extensive CNS hemorrhage and death on postcoital day (dpc) 12.5 (Okuda et al, 1996;Wang et al, 1996a,b;Sasaki et al, 1996). At least three isoforms of human AML1 proteins have been identi®ed, AML1 (also called AML1A), AML1b, and AML1c (also called AML1B).…”

Section: Introductionmentioning

confidence: 99%

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

et al. 1999

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A cytogenetically cryptic (12;21) translocation is the most common molecular abnormality identi®ed in childhood acute lymphoblastic leukemia (ALL), and it generates a chimeric TEL-AML1 protein. Fusion of the Helix-Loop-Helix (HLH) (also called the pointed) domain of TEL to AML1 has been suggested to convert AML1 from a transcriptional activator to a repressor. To de®ne the structural features of this chimeric protein required for repression, we analysed the transcriptional activity of a series of TEL-AML1 mutants on the AML1-responsive interleukin-3 (IL-3) promoter, a potentially relevant gene target. Our results demonstrate that TEL-AML1 represses basal IL-3 promoter activity in lymphoid cells, and deletion mutant analysis identi®ed three distinct domains of TEL-AML1 that are required for repression; the HLH (pointed) motif contained in the TEL portion of TEL-AML1, and both the runt homology domain (Rhd) and the 74 amino acids downstream of the Rhd that are present in the AML1 portion of the fusion protein. Although AML1B (and a shorter AML1 isoform, AML1A) have transcriptional activating activity on the IL-3 promoter, fusion of the AML1 gene to the TEL gene generates a repressor of IL-3 expression. Consistent with this activity, freshly isolated human ALL cells that contain TEL-AML1 do not express IL-3.

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“…The a subunit, with DNA binding properties, contains a region of homology with the runt gene of Drosophila (Daga et al, 1992) and the b subunit stabilizes the binding of the a subunit to DNA. Recent work has demonstrated that both subunits are essential for a correct hematopoiesis (Okuda et al, 1996;Wang et al, 1996a,b;Castilla et al, 1996;Sasaki et al, 1996;Yergeau et al, 1997;Niki et al, 1997) and that their disruption may be crucial for leukemogenesis. Other genes are found involved together with the CBF genes in di erent leukemia subtypes.…”

Section: Introductionmentioning

confidence: 99%

Subcellular localization of the oncoprotein MTG8 (CDR/ETO) in neural cells

et al. 1998

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The t(8;21) translocation associated with acute myeloid leukemia (AML) disrupts two genes, the AML1 gene also known as the core binding factor A2 (CBFA2) on chromosome 21, and a gene on chromosome 8, hereafter referred to as MTG8, but also known as CDR and ETO. Extensive information is available on AML1, a member of the CBF family of transcription factors, containing a highly conserved domain, the runt box, of the Drosophila segmentation gene runt. This gene is essential for the hematopoietic development and is found disrupted in several leukemias. In contrast, the function of the MTG8 gene is poorly understood. The predicted protein sequence shows two unusual, putative zinc-®ngers, three proline-rich regions, a PEST domain and several phosphorylation sites. In addition, we found a region encompassing aa 443 ± 514 predicted to have a signi®cant propensity to form coiled coil structures. MTG8 displays a high degree of similarity with nervy, a homeotic target gene of Drosophila, expressed in the nervous system. Human and mouse wild-type MTG8 are also highly expressed in brain relative to other tissues. For these reasons, we set out to investigate the expression and subcellular localization of the MTG8 protein in neural cells. Immunohistochemical experiments in a 12.5-dayold mouse embryo clearly showed that the protein was expressed in the neural cells of the developing brain and the spinal cord. In primary cultures of hippocampal neurons of 2 ± 3 day-old mice, MTG8 was found in the nucleus, in the cytoplasm and as ®ne granules in the neurites. Cytoplasmic localization of the protein was observed in Purkinje cells of both human and mouse cerebellum. The molecular mass of MTG8 in total human and mouse brain was analysed by immunoblotting and determined to be between 70 and 90 kDa. Isoforms with the same molecular mass were demonstrated in synaptosomes isolated from mouse forebrain. The evidence of MTG8 in the nucleus and cytoplasm of neural cells suggests a speci®c mechanism regulating the subcellular localization of the protein.

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Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta.

Cited by 353 publications

References 35 publications

The t(8;21) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1

The t(8;21) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

Subcellular localization of the oncoprotein MTG8 (CDR/ETO) in neural cells

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