The Capacity of Polyomavirus Enhancer Binding Protein 2αB (AML1/Cbfa2) To Stimulate Polyomavirus DNA Replication Is Related to Its Affinity for the Nuclear Matrix

Chen, Lin Feng; Ito, Kosei; Murakami, Yota; Ito, Yoshiaki

doi:10.1128/mcb.18.7.4165

Cited by 38 publications

(42 citation statements)

References 58 publications

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“…The leukemia-related AML1 and promyelocytic leukemia proteins have previously been identified as nuclear matrixassociated factors, consistent with recent findings by others (23,34). Here we report that AML1͞ETO and ETO are also nuclear matrix associated.…”

Section: Discussionsupporting

confidence: 93%

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The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFα2 transcription factor

McNeil

Zeng

Harrington

et al. 1999

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

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Targeting of gene regulatory factors to specific intranuclear sites may be critical for the accurate control of gene expression. The acute myelogenous leukemia 8;21 (AML1͞ETO) fusion protein is encoded by a rearranged gene created by the ETO chromosomal translocation. This protein lacks the nuclear matrix-targeting signal that directs the AML1 protein to appropriate gene regulatory sites within the nucleus. Here we report that substitution of the chromosome 8-derived ETO protein for the multifunctional C terminus of AML1 precludes targeting of the factor to AML1 subnuclear domains. Instead, the AML1͞ETO fusion protein is redirected by the ETO component to alternate nuclear matrix-associated foci. Our results link the ETO chromosomal translocation in AML with modifications in the intranuclear trafficking of the key hematopoietic regulatory factor, AML1. We conclude that misrouting of gene regulatory factors as a consequence of chromosomal translocations is an important characteristic of acute leukemias. M odifications in nuclear morphology are a hallmark of tumor cells and are used for diagnosis. However, there is limited knowledge of the subnuclear changes that accompany or contribute to tumor-related alterations of nuclear architecture. Biochemical evidence indicates that the protein composition of the nuclear matrix is modified in tumor cells (1-7). The nuclear matrix is a scaffold that provides a means for localizing genes and regulatory factors throughout the nuclear space (8-11). Consequently, analysis of targeting signals that direct regulatory factors to nuclear matrix-associated subnuclear sites (12) may provide insight into nuclear structure-function relationships that are compromised in cancer.The acute myelogenous leukemia (AML) transcription factor AML1 1 is a key regulator of hematopoiesis (13,14). Numerous cytogenetic abnormalities that involve genes encoding AML1 or its partner core binding factor ␤ have been identified in AML and acute lymphocytic leukemia (15-18). The frequent 8;21 translocation produces a chimeric protein (AML1͞ETO) in which the C terminus of AML1 is replaced by the unrelated ETO (MTG8) protein (19-23). The 8;21 translocation occurs in approximately 15% of AML in adult patients (24-26).The normal form of the AML1 protein has an N-terminal region containing a runt homology DNA-binding domain (27) and a multifunctional C-terminal region that supports transactivation, repression, and intranuclear targeting (28-34). Alternative splicing of the AML1 gene can generate several protein isoforms. The predominant isoform AML1B (480 aa) contains a 31-aa nuclear matrix-targeting signal (NMTS) in the C terminus. This targeting signal is necessary and sufficient to direct the factor to nuclear matrix-associated subnuclear sites that support transcription (30). Many of these AML1 sites are localized together with the hyperphosphorylated active form of RNA polymerase II o , and this association requires the presence of the runt homology domain of AML1B (35).The AML1͞ETO fusion product is expre...

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Section: Discussionsupporting

confidence: 93%

“…The normal form of the AML1 protein has an N-terminal region containing a runt homology DNA-binding domain (27) and a multifunctional C-terminal region that supports transactivation, repression, and intranuclear targeting (28)(29)(30)(31)(32)(33)(34). Alternative splicing of the AML1 gene can generate several protein isoforms.…”

mentioning

confidence: 99%

The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFα2 transcription factor

McNeil

Zeng

Harrington

et al. 1999

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

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“…The region between residues 1 and 49 prevents the Runt domain from interacting with either PEBP2␤ or DNA. transcription inhibition domain, TE1, 2 and 3: transcription activation elements, NLS: nuclear localization signal, NRDBn and NRDBc: negative regulatory region for DNA binding, located at N-terminal, and C-terminal sides, respectively, NRHn and NRHc: negative regulatory region for heterodimerization, located at N-terminal and C-terminal sides, respectively, Nuclear Matrix Association: the region tightly associated with nuclear matrix (Chen et al 1998), PPPY: so called PY motif to which WW-domain containing Yes associated protein (YAP) binds (Yagi et al 1999), Smads 1, 2, 3, 5: the region responsible for interaction with Smad1, Smad2, Smad3 and Smad5 (Hanai et al 1999), p300: the region responsible for interaction with p300 (Kitabayashi et al 1998a), Ear-2: the region responsible for interaction with Ear-2 (Ahn et al 1998), MAPK: two serine residues phosphorylated by MAP kinase (Tanaka et al 1996).…”

Section: Autoinhibition Of Dna Binding and Heterodimerizationmentioning

confidence: 99%

“…The nuclear matrix seems to be particularly important in this respect. We observed that the initiation of polyomavirus (Py) DNA replication takes place in the nuclear matrix and requires transcription factors including ␣B/AML1 (Chen et al 1998). We also showed that the association of ␣B/AML1 with the nuclear matirix is essential for initiation of PyDNA replication (Chen et al 1998), and noted that, although many transcription factors are associated with the nuclear matrix, they are not always located in the same compartment.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…We observed that the initiation of polyomavirus (Py) DNA replication takes place in the nuclear matrix and requires transcription factors including ␣B/AML1 (Chen et al 1998). We also showed that the association of ␣B/AML1 with the nuclear matirix is essential for initiation of PyDNA replication (Chen et al 1998), and noted that, although many transcription factors are associated with the nuclear matrix, they are not always located in the same compartment. One provocative possibility is that PEBP2 may recruit other transcription factors to specific compartments in which expression of specific, critical genes is required at particular stages in embryogenesis.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Molecular basis of tissue‐specific gene expression mediated by the Runt domain transcription factor PEBP2/CBF

1999

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The Runt domain transcription factor PEBP2/CBF is a heterodimer of ␣ and ␤ subunits. Of the three mammalian ␣ subunit genes, which are homologues of the Drosophila gene runt, PEBP2␣A/CBFA1 and PEBP2␣B/AML1 are critical regulators of osteogenesis and haematopoiesis, respectively. A unique functional interaction between PEBP2␣B/AML1 and Ets-1 was recently observed, and provides a clear example of context-dependent transcriptional regulation. An elaborate mechanism of cooperation between the two factors may represent a basis for tissuespecific gene expression, which is thought to be achieved by combinations of specific sets of transcription factors unique to each cell lineage or stage of differentiation. A possible molecular basis for the critical role(s) played by PEBP2/CBF in tissue determination is discussed in light of these observations.

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Transcriptional control within the three-dimensional context of nuclear architecture: Requirements for boundaries and direction

et al. 1999

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Evidence is accruing that the architectural organization of nucleic acids and regulatory proteins within the cell nucleus support functional interrelationships between nuclear structure and gene expression. The punctate distribution of several transcription factors has provided several paradigms for pursuing mechanisms that direct these regulatory proteins to subnuclear sites where gene activation or suppression occurs. Sequences that are necessary and sufficient to direct regulatory proteins to transcriptionally active nuclear domains have been identified. Mutations that disrupt intranuclear targeting signals lead to modified subnuclear distribution of transcription factors and aberrant expression in tumor cells. J. Cell. Biochem. Suppls. 32/33:24-31, 1999Suppls. 32/33:24-31, . 1999 Wiley-Liss, Inc. Key words: AML/CBFA; gene expression; intranuclear targeting; subnuclear domainsTranscriptional control requires linkage of signaling pathways that exchange regulatory information between the nucleus and cytoplasm as well as within the cell nucleus. Gene promoters provide regulatory infrastructure by functioning as blueprints for responsiveness to the flow of cellular regulatory signals. Selective utilization of the information supports transient developmental and long-term phenotypic expression of genes. As the regulatory sequences and factors that activate or suppress transcription are identified and characterized, several fundamental paradoxes surface. How can a gene with a single promoter meet the selective requirements for expression under diverse biological circumstances? How, with a limited repertoire of promoter elements and cognate regulatory factors, can a threshold be attained to initiate or downregulate transcription in nuclei of intact cells? How are the regulatory activities that reside at independent promoter domains integrated?There is increasing acceptance that components of nuclear architecture support the organization and sorting of regulatory information in a manner that facilitates selective utilization. The primary level of nuclear organization, the representation and ordering of genes and promoter elements, provides alternatives for physiological control. The modular arrangement of regulatory elements and overlap of regulatory sequences within promoter domains and the multipartite composition of regulatory complexes increases options for responsiveness. Chromatin structure and nucleosome organization reduces distances between regulatory sequences, facilitates crosstalk between promoter elements, and renders elements competent for interactions with positive and negative regulatory factors. The components of higher-order nuclear architecture that includes nuclear pores, the nuclear matrix and subnuclear domains contribute to the subnuclear distribution and activities of genes and regulatory factors.There is emerging recognition that nuclear structure and function are causally interrelated. With accruing evidence for organization

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The Capacity of Polyomavirus Enhancer Binding Protein 2αB (AML1/Cbfa2) To Stimulate Polyomavirus DNA Replication Is Related to Its Affinity for the Nuclear Matrix

Cited by 38 publications

References 58 publications

The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFα2 transcription factor

The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFα2 transcription factor

Molecular basis of tissue‐specific gene expression mediated by the Runt domain transcription factor PEBP2/CBF

Transcriptional control within the three-dimensional context of nuclear architecture: Requirements for boundaries and direction

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