ETO interacting proteins

Hug, Bruce A.; Lazar, Mitchell A.

doi:10.1038/sj.onc.1207674

Cited by 98 publications

(83 citation statements)

References 48 publications

(140 reference statements)

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“…This is not to say that the DNA-binding domain of AML1-ETO can never serve to deliver coregulatory factors to an AML1 DNA-binding locus; rather, DNA binding may not be the primary mode by which AML1-ETO influences gene expression during development. To explore this view of AML1-ETO further, the biochemical and structural basis for the interaction between AML1-ETO and its binding partners needs to explored (reviewed in Hug and Lazar, 2004). Since multiple binding sites for the corepressor N-CoR have been identified within ETO (Lausen et al, 2004), which overlap with binding sites for activators of the E box family , these factors become good candidates for the analysis of biochemical mechanism(s) by which AML1-ETO alters patterns of gene expression during development.…”

Section: Aml1-eto Does Not Repress Ela2mentioning

confidence: 99%

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

et al. 2005

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A 117 bp fragment of the human ELA2 promoter has been characterized that can act as a minimal promoter for the expression of neutrophil elastase. Chromatin immunoprecipitation and siRNAs revealed that expression of ELA2 is regulated by the acute myeloid human leukemia 1 protein (AML1), C/EBPa, PU.1 and c-Myb transcription factors. ELA2 has also been investigated as a possible target of the leukemic fusion protein AML1-ETO resulting from the t(8;21) chromosomal translocation. AML1-ETO, like AML1, binds the ELA2 promoter in the myeloid cell lines Kasumi-1 and U937, but unexpectedly fails to significantly alter expression of ELA2. Although AML1-ETO downregulates the expression of C/EBPa, changes in C/EBPa expression do not correlate with changes in the expression of ELA2. Our observations indicate that AML1-ETO may not be a constitutive repressor of gene expression in every case in which it can associate with DNA, either on its own or in conjunction with C/EBPa. Since neither ETO nor AML1-ETO are typically expressed in hematopoietic progenitors, we hypothesize that it is the interactions between AML1-ETO and regulatory cofactors in disease-state cells that alter gene expression programs during hematopoiesis. These protein-protein interactions may not require simultaneous DNA binding by AML1-ETO for the deleterious effects of the fusion protein to be realized.

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Section: Aml1-eto Does Not Repress Ela2mentioning

confidence: 99%

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

et al. 2005

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“…The NHR domains serve as docking interface for a variety of different proteins, including the E-protein HEB, 5,6 the apoptosis-related protein SON, 7 and nuclear corepressor proteins, such as N-CoR, SMRT, mSIN3A, and MTGR1, as well as histone deacetylases (HDACs). [8][9][10][11] In addition, the NHR2 domain mediates tetramer formation through hydrophobic and ionic/polar interactions. Two ␣-helices align in a head-to-tail fashion to form an antiparallel dimer.…”

Section: Introductionmentioning

confidence: 99%

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

Wichmann

Becker

Chen-Wichmann

et al. 2010

Blood

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RUNX1/ETO, the fusion protein resulting from the chromosomal translocation t(8;21), is one of the most frequent translocation products in acute myeloid leukemia. Several in vitro and in vivo studies have shown that the homo-tetramerization domain of ETO, the nervy homology region 2 (NHR2), is essential for RUNX1/ETO oncogenic activity. We analyzed the energetic contribution of individual amino acids within the NHR2 to RUNX1/ETO dimertetramer transition and found a clustered area of 5 distinct amino acids with strong contribution to the stability of tetramers. Substitution of these amino acids abolishes tetramer formation without affecting dimer formation. Similar to RUNX1/ ETO monomers, dimers failed to bind efficiently to DNA and to alter expression of RUNX1-dependent genes. RUNX1/ETO dimers do not block myeloid differentiation, are unable to enhance the selfrenewal capacity of hematopoietic progenitors, and fail to induce leukemia in a murine transplantation model. Our data reveal the existence of an essential structural motif (hot spot) at the NHR2 dimertetramer interface, suitable for a molecular intervention in t(8;21) leukemias. IntroductionChromosomal translocations are frequent events during malignant cell transformation, particularly during leukemogenesis. 1 The translocation t(8;21), one of the most frequent chromosomal anomalies in acute myeloid leukemia (AML), involves the RUNX1 gene (also known as AML1, CBF␣2, or PEBP2␣B) on chromosome 21 and the ETO gene (also known as MTG8 or RUNX1T1) on chromosome 8. The ubiquitously expressed RUNX1 is a transcription factor and belongs to the key regulators of hematopoietic cell differentiation. 2 The fusion protein RUNX1/ETO contains the DNA-binding domain (Runt, RHD) of the RUNX1 transcription factor but lacks the C-terminal transactivation sequence that is replaced by almost the entire ETO protein. 2 forms of RUNX1/ETO coexist in AML-leukemia samples: the originally discovered full-length RUNX1/ETO and a splice variant called RUNX1/ETO9a, which lacks 178 amino acids at the C-terminus. Only RUNX1/ETO9a does not require cooperative events for inducing leukemia development in mice. 3,4 We and others have shown that RUNX1/ETO has a modular structure. Besides the Runt domain, RUNX1/ETO contains 4 functional domains, which are generally referred to as nervy homology region (NHR1 to NHR4). The NHR domains serve as docking interface for a variety of different proteins, including the E-protein HEB, 5,6 the apoptosis-related protein SON, 7 and nuclear corepressor proteins, such as N-CoR, SMRT, mSIN3A, and MTGR1, as well as histone deacetylases (HDACs). [8][9][10][11] In addition, the NHR2 domain mediates tetramer formation through hydrophobic and ionic/polar interactions. Two ␣-helices align in a head-to-tail fashion to form an antiparallel dimer. Two dimers subsequently are positioned on top of each other in a sandwich-like fashion. The total interaction area composing all contact points of the 4 ␣-helices is approximately 10 000 Å. 2 Substitution of 7 leucines withi...

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“…In WT cells CBF regulates chromatin remodeling of target genes by recruiting coactivators and histone acetyl transferases (6). In t(8;21) cells, the AML1-ETO fusion still binds CBF target DNA sequences through the AML1 DNA-binding domain; however, the ETO fusion partner functionally dominates by recruiting proteins involved in chromatin repression (e.g., corepressors and histone deacetylases) (1,7). The formation of a corepressor complex involving AML1-ETO serves to shut down gene expression of genes normally activated by CBF.…”

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confidence: 99%

The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain

Plevin

Zhang

Guo

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Up to 15% of acute myeloid leukemias (AMLs) are characterized by the abnormal expression of the eight-twenty-one (ETO) transcriptional corepressor within an AML1-ETO fusion protein. The t(8;21) chromosomal translocation serves not only to disrupt WT AML1 function but also to introduce ETO activity during hematopoiesis. AML1-ETO was recently shown to inhibit E protein transactivation by physically displacing WT coactivator proteins in an interaction mediated by ETO. Here, we present the 3D solution structure of the human ETO TAFH (eTAFH) domain implicated in AML1-ETO:E protein interactions and report an unexpected fold similarity to paired amphipathic helix domains from the transcriptional corepressor Sin3. We identify and characterize a conserved surface on eTAFH that is essential for ETO:E protein recognition and show that the mutation of key conserved residues at this site alleviates ETObased silencing of E protein transactivation. Our results address uncharacterized aspects of the corepression mechanism of ETO and suggest that eTAFH may serve to recruit ETO (or AML1-ETO) to DNA-bound transcription factors. Together, these findings imply that a cofactor exchange mechanism, analogous to that described for E protein inhibition, may represent a common mode of action for ETO.corepressor ͉ NMR ͉ protein structure ͉ sin3 C ore binding factor (CBF) is an essential hematopoietic transcriptional regulator that is frequently mutated in acute myeloid leukemias (AMLs) (1, 2). In up to 15% of AML cases, a translocation between chromosomes 8 and 21 replaces a portion of the gene encoding the CBF subunit AML1 with a gene specifying an unrelated corepressor protein, eight-twenty-one (ETO) (3, 4). The subsequent fusion protein, AML1-ETO, contains the DNA-binding domain from AML1 fused to most of ETO. Expression of this chimeric protein and the consequent disruption of WT AML1 function are key events in the production of an AML phenotype (5). In WT cells CBF regulates chromatin remodeling of target genes by recruiting coactivators and histone acetyl transferases (6). In t(8;21) cells, the AML1-ETO fusion still binds CBF target DNA sequences through the AML1 DNA-binding domain; however, the ETO fusion partner functionally dominates by recruiting proteins involved in chromatin repression (e.g., corepressors and histone deacetylases) (1, 7). The formation of a corepressor complex involving AML1-ETO serves to shut down gene expression of genes normally activated by CBF.As an alternative or complementary mechanism involving distinct target genes, recent studies have shown that AML1-ETO can silence E protein transactivation (8). E proteins comprise a family of widely expressed transcription factors involved in regulating cell growth, differentiation, and apoptosis (9-11). DNA-bound E proteins interact with the histone acetyl transferase p300͞CREB binding protein, leading to histone modifications that facilitate transcription initiation (8, 12). However, AML1-ETO very strongly interacts with E proteins through an N-terminal activation...

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ETO interacting proteins

Cited by 98 publications

References 48 publications

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain

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