The runt domain identifies a new family of heterometric transcriptional regulators

Kagoshima, Hiroshi; Shigesada, Katsuya; Satake, Masanobu; Ito, Yoshiaki; Miyoshi, Hiroyuki; Ohki, Masafumi; Pepling, Melissa E.; Gergen, Peter J.

doi:10.1016/0168-9525(93)90026-e

Cited by 320 publications

(228 citation statements)

References 18 publications

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“…The translocation results in the production of a fusion protein that consists of 177 amino acids of RUNX1 containing the Runt domain fused to 575 amino acids of RUNX1T1 (also known as ETO or MTG8). The Runt domain is involved in DNA binding and heterodimerization with CBFb (Kagoshima et al, 1993) whereas RUNX1T1 can interact with several transcriptional co-repressors (Amann et al, 2001). As a result, the RUNX1-RUNX1T1 fusion protein can recruit transcriptional co-repressor complexes to RUNX1 binding sites and thus represses RUNX1 target genes (Linggi et al, 2002;Follows et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.

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Section: Introductionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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“…CBF is a heterodimeric transcription factor composed of two subunits, a and b (Kagoshima et al, 1993). 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.…”

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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“…(Kamachi et al, 1990;Ogawa et al, 1993a,b;Wang and Speck, 1992;Wang et al, 1993). The Runt domain, which is conserved among the a subunit-encoding genes, is responsible for DNA binding activity and heterodimer formation with the b polypeptide Kagoshima et al, 1993;Meyers et al, 1993;Ogawa et al, 1993b). On the other hand, the b subunit dimerizes with the a subunit to enhance its DNA binding a nity, but does not show any intrinsic DNA-binding activity by itself (Ogawa et al, 1993a;Wang et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

The protooncogene product, PEBP2β/CBFβ, is mainly located in the cytoplasm and has an affinity with cytoskeletal structures

et al. 1997

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The runt domain identifies a new family of heterometric transcriptional regulators

Cited by 320 publications

References 18 publications

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

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

The protooncogene product, PEBP2β/CBFβ, is mainly located in the cytoplasm and has an affinity with cytoskeletal structures

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