Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins

Sun, Weifeng; Graves, Barbara J.; Speck, Nancy A.

doi:10.1128/jvi.69.8.4941-4949.1995

Cited by 138 publications

(50 citation statements)

References 80 publications

(123 reference statements)

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“…7), argues for this possibility. It would also be in line with reports that AML1 and Ets1 can cooperate in DNA binding at adjacent binding sites [17,29].…”

Section: Discussionsupporting

confidence: 90%

AML and Ets proteins regulate the Iα1 germ-line promoter

et al. 1999

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The immunoglobulin heavy chain (IgH) class switch recombination of B lymphocytes preferentially targets unrearranged IgH genes that have already been rendered transcriptionally active. Transcription of the germ-line IgH genes is controlled by intervening (I) regions upstream of their switch regions. The I alpha1 promoter activates transcription of the human germ-line C alpha1 gene for IgA1 and mediates the transforming growth factor (TGF)-beta1 responsiveness of this locus. Here we show that the I alpha1 promoter contains several binding sites for the AML/PEBP2/CBF family of transcription factors and that AML and Ets proteins are major regulators of the basal and TGF-beta-inducible promoter activity. Our data constitute a starting point for studies to elucidate the molecular mechanism by which TGF-beta regulates IgA production.

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“…7), argues for this possibility. It would also be in line with reports that AML1 and Ets1 can cooperate in DNA binding at adjacent binding sites [17,29].…”

Section: Discussionsupporting

confidence: 90%

AML and Ets proteins regulate the Iα1 germ-line promoter

et al. 1999

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“…ETS proteins interact with several protein partners. ETS-1 interacts with the basic region of c-JUN through its ETS domain (2), and ELK-1, SAP-1, and NET interact with SRF through an identified protein interaction domain, the B domain (44). The 120-amino-acid region of MEF that interacts with AML1 does not overlap the ETS domain, nor is it homologous to previously defined protein-protein interacting domains.…”

Section: Discussionmentioning

confidence: 99%

Functional and Physical Interactions between AML1 Proteins and an ETS Protein, MEF: Implications for the Pathogenesis of t(8;21)-Positive Leukemias

Mao

Frank

Zhang

et al. 1999

Molecular and Cellular Biology

117

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The AML1 and ETS families of transcription factors play critical roles in hematopoiesis; AML1, and its non-DNA-binding heterodimer partner CBFbeta, are essential for the development of definitive hematopoiesis in mice, whereas the absence of certain ETS proteins creates specific defects in lymphopoiesis or myelopoiesis. The promoter activities of numerous genes expressed in hematopoietic cells are regulated by AML1 proteins or ETS proteins. MEF (for myeloid ELF-1-like factor) is a recently cloned ETS family member that, like AML1B, can strongly transactivate several of these promoters, which led us to examine whether MEF functionally or physically interacts with AML1 proteins. In this study, we demonstrate direct interactions between MEF and AML1 proteins, including the AML1/ETO fusion protein, in t(8;21)-positive acute myeloid leukemia (AML) cells. Using mutational analysis, we identified a novel ETS-interacting subdomain (EID) in the C-terminal portion of the Runt homology domain (RHD) in AML1 proteins and determined that the N-terminal region of MEF was responsible for its interaction with AML1. MEF and AML1B synergistically transactivated an interleukin 3 promoter reporter gene construct, yet the activating activity of MEF was abolished when MEF was coexpressed with AML1/ETO. The repression by AML1/ETO was independent of DNA binding but depended on its ability to interact with MEF, suggesting that AML1/ETO can repress genes not normally regulated by AML1 via protein-protein interactions. Interference with MEF function by AML1/ETO may lead to dysregulation of genes important for myeloid differentiation, thereby contributing to the pathogenesis of t(8;21) AML.

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“…This observation suggests that AML1/CBFb functions as a transcriptional organizer that recruits tissue-speci®c factors into a nucleoprotein complex, or enhancesome, that stimulates lineage-restricted transcription (Carey, 1998). In support of this interpretation, AML1 has been shown to synergistically activate transcription of the TCRb and TCRa enhancers with Ets1 (Giese et al, 1995;Sun et al, 1995), the NP-3 promoter with C/EBP-a (Westerdorf et al, 1998) and the CSF-1R promoter with both C/EBP-a and PU.1 (Petrovick et al, 1998). Each of these activities appears to involve a direct physical interaction between AML1 and the cooperating transcription factor, resulting in both enhanced DNA binding of each factor and the generation of an activation surface that facilitates interactions with both coactivators and the basal transcriptional machinery (Carey, 1998).…”

Section: Identi®cation Of Genes Targeted By T(8;21)mentioning

confidence: 91%

The Aml1‐eto Chimaeric Transcription Factor in Acute Myeloid Leukaemia: Biology and Clinical Significance

1999

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Acute myeloid leukaemia (AML) is a heterogenous disease, with individual cases showing variability in clinical presentation, blast cell morphology, therapeutic response and long-term prognosis. This heterogeneity extends to the molecular genetic lesions underlying the pathogenesis of AML. Although nonrandom clonal chromosomal aberrations are present in the majority of cases, each abnormality affects only a limited subset of cases. Nonetheless, recent studies have demonstrated that several chromosomal rearrangements, and the molecular abnormalities they produce, identify distinct patient subgroups with predictable clinical features and therapeutic responses.One of the most frequent cytogenetic abnormalities in AML is t(8;21)(q22;q22). The cloning of the genes targeted by this translocation led to the identi®cation of AML1 as the DNA-binding subunit of the AML1/CBFb core binding factor transcription complex, a critical regulator of normal haemopoiesis. Subsequent studies have demonstrated that the genes encoding this transcription factor complex are the most common targets of chromosomal rearrangements in human leukaemia. In this review I will summarize our understanding of the normal function of AML1/CBFb in haemopoiesis, and will then describe the mechanism through which t(8;21) induces leukaemia. Throughout I will emphasize the clinical signi®cance of this genetic lesion and the general principles of haemopoietic transformation that have emerged from study of the activity of the encoded chimaeric oncoprotein. Clinical features associated with t(8;21)-containing leukaemiaThe t(8;21) translocation is found in approximately 10±15% of AML cases and is frequently the only cytogenetic abnormality present in the leukaemic blasts (Hagemeijer et al, 1984;Bitter et al, 1987). Patients with this subtype of AML typically present with FAB AML-M2 morphology, in which the leukaemic blasts have prominent Auer rods, strong myeloperoxidase positivity, homogenous salmoncoloured granules, cytoplasmic vacuolization, and prominent bone marrow eosinophilia (Bitter et al, 1987). In addition, the leukaemic blasts frequently have a distinct immunophenotype, characterized by positivity for the B-cellassociated marker CD19, as well as CD13, CD34 and CD56 positivity (Hurwitz et al, 1992). This combination of ®ndings strongly suggests the presence of t(8;21). In fact, > 90% of t(8;21)-containing leukaemias have FAB AML-M2 morphology, and as many as 30±40% of FAB-M2 cases have this chromosomal translocation (Hagemeijer et al, 1984;Bitter et al, 1987). Interestingly, t(8;21)-containing leukaemias frequently form extramedullary tumours or chloromas (Swirsky et al, 1984). Despite this tendency for bulk disease, the presence of t(8;21) is associated with a high remission rate and prolonged disease-free survival in patients treated with standard induction and consolidation chemotherapy (Bloom®eld et al, 1998;Grimwade et al, 1998). Identi®cation of genes targeted by t(8;21)The 8;21 translocation was molecularly cloned in 1991 and shown to rearrang...

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Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins

Cited by 138 publications

References 80 publications

AML and Ets proteins regulate the Iα1 germ-line promoter

AML and Ets proteins regulate the Iα1 germ-line promoter

Functional and Physical Interactions between AML1 Proteins and an ETS Protein, MEF: Implications for the Pathogenesis of t(8;21)-Positive Leukemias

The Aml1‐eto Chimaeric Transcription Factor in Acute Myeloid Leukaemia: Biology and Clinical Significance

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