FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci

Alm-Kristiansen, Anne Hege; Sæther, Thomas; Matre, Vilborg; Gilfillan, Siv; Dahle, Øyvind; Gabrielsen, Odd S.

doi:10.1038/onc.2008.105

Cited by 54 publications

(54 citation statements)

References 43 publications

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“…22 Shortly thereafter, Cajal bodies and HLBs were shown to be distinct structures also in mammalian cells. 23,24 Although Coilin is sometimes observed at HLBs in both Drosophila and mammalian cells, 16,[25][26][27] HLBs that do not contain Coilin are frequently observed. Moreover, genetic experiments show that HLB assembly occurs normally in the absence of Coilin.…”

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confidence: 99%

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

2017

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Metazoan replication-dependent (RD) histone genes encode the only known cellular mRNAs that are not polyadenylated. These mRNAs end instead in a conserved stem-loop, which is formed by an endonucleolytic cleavage of the pre-mRNA. The genes for all 5 histone proteins are clustered in all metazoans and coordinately regulated with high levels of expression during S phase. Production of histone mRNAs occurs in a nuclear body called the Histone Locus Body (HLB), a subdomain of the nucleus defined by a concentration of factors necessary for histone gene transcription and premRNA processing. These factors include the scaffolding protein NPAT, essential for histone gene transcription, and FLASH and U7 snRNP, both essential for histone pre-mRNA processing. Histone gene expression is activated by Cyclin E/Cdk2-mediated phosphorylation of NPAT at the G1-S transition. The concentration of factors within the HLB couples transcription with pre-mRNA processing, enhancing the efficiency of histone mRNA biosynthesis. KEYWORDSCell cycle; Drosophila; histone genes; mRNA processing; nuclear bodyProper utilization of genetic information in eukaryotes requires extensive three-dimensional organization of the genome and its associated proteins within the nucleus. The basic unit of genome organization is the nucleosome, an octamer of two molecules of each of the four core histone proteins (H2A, H2B, H3 and H4) that packages »147 base pairs of DNA. In mammalian cells, approximately 4£10 8 molcules of each core histone must be synthesized during S phase of the cell cycle to package the newly replicated DNA. Defects in this process result in genome instability that can contribute to human pathologies like cancer. Histone protein synthesis results from a large increase in production at the beginning of S phase of equal amounts of mRNAs encoding the four core nucleosomal histones, as well as histone H1. This highly coordinated gene expression event is performed by a set of transcription and pre-mRNA processing factors unique to replication dependent (RD) histone mRNA biosynthesis that assemble into a nuclear body tightly associated with RD histone genes called the histone locus body (HLB). HLB formation involves a combination of ordered and stochastic assembly steps, and cell cycle regulated changes in the HLB occur to activate histone gene expression during S phase. Here we describe the history of how the HLB was discovered followed by a discussion of HLB assembly mechanism and how the HLB functions in RD histone mRNA biosynthesis.

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Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

2017

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“…Moreover, the transcriptional regulatory activity of Myb is crucial for its transforming ability (Gonda et al, 1989;Lane et al, 1990;Hu et al, 1991). Multiple co-factors like p300/CBP, Mi-2a, FLASH and menin/MLL engage in the regulation of the transactivational activity of c-Myb (Dai et al, 1996;Oelgeschlager et al, 1996;Kasper et al, 2002;Saether et al, 2007;Alm-Kristiansen et al, 2008;Jin et al, 2010). Recently, the importance of coactivation by p300 in myeloid transformation was highlighted using a novel murine hematopoietic cell line transformation assay (Pattabiraman et al, 2009).…”

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A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

et al. 2010

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“…Structural studies confirmed interaction between the TAD of c-Myb and the KIX domain of CBP (39), whereas disruption of this interaction by mutation perturbs hematopoiesis in vivo (5). Recent reports have also identified two novel coactivators, Mi-2α and FLASH, which interact with Myb through its DBD and NRD (40,41). c-Myb also interacts with the corepressors mSin3a, c-Ski, N-CoR, and Tif-1β through the NRD and the R2 and R3 repeats of the DBD (Fig.…”

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Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability

Pattabiraman

Sun

Dowhan

et al. 2009

Molecular Cancer Research

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The c-myb proto-oncogene is a key regulator of hematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in, and is required for the proliferation of, most human myeloid and acute lymphoid leukemias. Recently, chromosomal translocation and genomic duplications of c-MYB have been identified in human T-cell acute leukemia. The present work focuses on the effects of mutations in different domains of the murine c-Myb protein on its transforming ability as defined by suppression of myelomonocytic differentiation and continued proliferation. Using both a novel myeloid cell line-based assay and a primary hematopoietic cell assay, we have shown that mutation of single residues in the transactivation domain important for CBP/p300 binding leads to complete loss of transforming ability. We also simultaneously mutated residues in the DNA-binding domain and the negative regulatory domain of the protein. These double mutants, but not the corresponding single mutants, show a complete loss of transforming activity. Surprisingly, these double mutants show severely impaired transactivation and are also defective for CBP/ p300 binding. Our results imply that multiple Myb domains influence its interaction with CBP/p300, highlight the importance of this interaction for myeloid transformation, and suggest an approach for molecular targeting

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FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci

Cited by 54 publications

References 43 publications

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability

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