The AML1-MTG8 Leukemic Fusion Protein Forms a Complex with a Novel Member of the MTG8(ETO/CDR) Family, MTGR1

Kitabayashi, Issay; Ida, Kohmei; Morohoshi, Fumiko; Yokoyama, Akihiko; Mitsuhashi, Naoko; Shimizu, Kimiko; Nomura, Nobuo; Hayashi, Yasuhide; Ohki, Masafumi

doi:10.1128/mcb.18.2.846

Cited by 146 publications

(168 citation statements)

References 60 publications

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“…The complex marked with the arrowhead was supershifted such that it was unable to enter the gel when extracts were preincubated with polyclonal antibody to Tal1 (anti-Tal1) or a monoclonal antibody to p300 (RW128) (anti-p300) but not with a monoclonal antibody to a human c-Myc epitope (9E10) (anti-Myc epitope) or Tal1 preimmune immunoglobulin (Tal1 preimmune) p300 and TAL1 transcriptional activity S Huang et al 1998). While modest from a quantitative standpoint, the magnitude of p300-stimulated coactivation was comparable to that described for BETA-2 (Mutoh et al, 1998), Smad3 (Janknecht et al, 1998), and AML1 (Kitabayashi et al, 1998). Finally, no e ect of p300 was seen in cells transfected with the reporter plasmid alone (Figure 4).…”

Section: P300 Augments Transcription Stimulated By Tal1-e12 Heterodimerssupporting

confidence: 66%

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

et al. 1999

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Section: P300 Augments Transcription Stimulated By Tal1-e12 Heterodimerssupporting

confidence: 66%

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

et al. 1999

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“…A/E-D401, which lacks the C-terminal zinc ®nger domain and one proline-serine/threonine rich region, retains transforming potential, whereas A/E-D292 does not. Previous studies have shown that a mutant similar to A/E-D401 can repress TCRb enhancer activity, but that the A/E-D292 mutant does not repress transcription Kitabayashi et al, 1998). Neither of these mutants can upregulate BCL-2 promoter activity (Klampfer et al, 1996), suggesting that transforming activity correlates best with the ability of AML1/ETO to repress transcription of AML1B activated promoters.…”

Section: Discussionmentioning

confidence: 97%

“…Neither of these mutants can upregulate BCL-2 promoter activity (Klampfer et al, 1996), suggesting that transforming activity correlates best with the ability of AML1/ETO to repress transcription of AML1B activated promoters. A recent mutational analysis of AML1/ETO identi®ed the 292 ± 401 aa region as being essential for the ability of AML1/ETO to block the differentiation and G-CSF dependent proliferation of L-G murine myeloid progenitor cells and to interact with the MTGR1 protein (Kitabayashi et al, 1998). Thus, studies of AML1/ETO in numerous cell types demonstrate the importance of the 292 ± 401 a.a. region of AML1/ETO to its biological functions.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that truncation of AML1 at amino acid 177 is not su cient for its transcriptional regulatory properties (Uchida et al, 1997), and numerous functional domains have been identi®ed in the ETO portion of the fusion protein (Lutterbach et al, 1998;Kitabayashi et al, 1998). Several novel biologic functions acquired by the fusion protein were recently demonstrated in AML1/ETO knock-in and retrovirally transduced murine stem cell experiments, in which AML1/ETO expression resulted in dysplastic hematopoiesis and increased progenitor cell self-renewal capabilities.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence for an in vivo dominantnegative function of the fusion protein was provided by AML1/ETO knock-in experiments, which showed that mice heterozygous for AML1/ETO had the same phenotype as AML1 knock-out mice (Okuda et al, 1998;Yergeau et al, 1997). Consistent with a negative e ect on AML1 function, AML1/ETO has been shown to block both the di erentiation of myeloid progenitor cell lines and the ability of AML1 to activate myeloid speci®c promoters (Kitabayashi et al, 1998;Westendorf et al, 1998). In contrast to its role as a dominant inhibitor, AML1/ETO can activate the BCL-2 promoter in U937 cells, an e ect not seen when AML1 or ETO are overexpressed in these cells (Klampfer et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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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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Mammalian runt-domain proteins and their roles in hematopoiesis, osteogenesis, and leukemia

Westendorf¹,

Hiebert²

1999

J. Cell. Biochem.

116

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Mammalian Runt-domain-containing factors are structurally and functionally similar and have essential roles in hematopoiesis and osteogenesis. These factors can act as either positive or negative transcriptional regulators of tissue-specific genes whose promoters or enhancers contain the consensus Runt-domain binding element, TGT/CGGT. This sequence is necessary but not sufficient to regulate the transcription of a wide variety of genes. Runt-domain factors are promoter organizers that cooperate with neighboring factors and recruit transcriptional co-activators or co-repressors to regulate expression of tissue-specific genes. AML1 is required for hematopoiesis and is a frequent target of chromosomal translocations in acute leukemias. Fusion proteins generated by these translocations are dominant repressors of genes regulated by the Runt-domain factors. AML3 may also be involved in leukemogenesis. In addition, AML3 has an essential role in bone development, as it is required for osteoblast differentiation and is mutated in patients with cleidocranial dysplasia. J. Cell. Biochem. Suppls. 32/33:51-58, 1999. Key words: AML1; AML2; AML3; CBFA; PEPB2␣; ETO; leukemia; bone; osteoblasts; cleidocranial dysplasia; Runx Mammalian cells contain three genes that encode for proteins that share structural and functional similarity with the Drosophila protein, Runt. Each gene was cloned in multiple laboratories and thus has several names (Table I). We use the acute myeloid leukemia (AML) nomenclature in this review. The mammalian Runt-domain factors have required roles as transcriptional regulators of hematopoiesis and osteogenesis. Because of alternative exon usage, multiple isoforms of each mammalian gene product exist. Nevertheless, the mammalian factors are more than 50% identical at the amino acid level and greater than 93% identical within a 100-120 amino acid domain. This region is called the runt homology domain (RHD) because it is almost 70% identical to a region in Runt (Fig. 1). The RHD of human AML-1 mediates binding to the DNA sequence, TGT/CGGT, hereafter called the Runt domain binding element. This site was identified as the binding sequence for the Moloney murine leukemia virus core binding factor (CBF) and for polyoma enhancer binding protein 2 (PEBP2), which stimulates viral replication [reviewed by Lutterbach and Hiebert, 1999]. The RHD not only binds DNA but also mediates association with CBF␤, a protein that does not bind DNA itself but increases the affinity of the Runt-domain factors for DNA [reviewed by Lutterbach and Hiebert, 1999]. CBF␤ is the human homologue of the Drosophila proteins, Brother and Big Brother. Together with AML-1, CBF␤ forms a transcription factor complex that is one of the most common targets of chromosomal translocations in acute leukemia (Fig. 2).As a result of space constraints, we are unable to reference all original studies with these factors in this review. With apologies to the omitted authors, the reader is referred to other recent reviews for detailed descriptions of...

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The AML1-MTG8 Leukemic Fusion Protein Forms a Complex with a Novel Member of the MTG8(ETO/CDR) Family, MTGR1

Cited by 146 publications

References 60 publications

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

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

Mammalian runt-domain proteins and their roles in hematopoiesis, osteogenesis, and leukemia

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