The BAT1 gene in the MHC encodes an evolutionarily conserved putative nuclear RNA helicase of the DEAD family

Peelman, Luc; Chardon, Patrick; Nunes, Manoel; Renard, Christine; Geffrotin, Claudine; Vaiman, M.; Zeveren, Alex Van; Coppieters, Wouter; Weghe, Alex Van De; Bouquet, Y.; Choy, Wanda W.; Strominger, Jack L.; Spies, Thomas A.

doi:10.1016/0888-7543(95)80203-x

Cited by 51 publications

(33 citation statements)

References 33 publications

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“…BAT1 is thought to act as a negative regulator of inflammation (Allcock et al, 2001) with properties of RNA binding activity and translation initiation factor (Peelman et al, 1995;Allcock et al, 1999). Our result that BAT1 is downregulated in senescent HUVECs raises the possibility that reduction of BAT1 in senescent endothelial cells leads to predisposition to vascular inflammation.…”

Section: Discussionmentioning

confidence: 58%

Searching for Genes Involved in Arteriosclerosis: Proteomic Analysis of Cultured Human Umbilical Vein Endothelial Cells Undergoing Replicative Senescence

Kamino

Hiratsuka

Toda

et al. 2003

Cell Struct. Funct.

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ABSTRACT. It is known that replicative senescence of endothelium in vivo contributes at least partially to agerelated vascular disorders such as arteriosclerosis. However, the genes involved in this process remain to be identified. In this study, we employed a proteomics-based approach to identify candidate genes using in vitro cultured human umbilical vein endothelial cells (HUVECs) as an experimental model for replicative senescence. By comparing protein spots from young and senescent HUVECs using two-dimensional electrophoresis, we identified three up-regulated proteins and five down-regulated proteins in senescent HUVECs as compared to young HUVECs, whose alteration was not observed during replicative senescence of primary human fibroblasts. Consistent results were obtained in Western blotting analysis using specific antibodies raised against some of these proteins, whereas there were no significant changes in the mRNA levels of these genes during senescence of HUVECs. Among them, cathepsin B, a protease participating in both intracellular proteolysis and extracellular matrix remodeling was observed to be dramatically up-regulated in senescent HUVECs and whose activity is known to be up-regulated in atherosclerotic lesions with senescence-associated phenotypes in vivo. Additional proteins, including cytoskeletal proteins and proteins involved in the processes of synthesis, turnover and modification of protein, were identified, whose function in endothelium was previously unsuspected. These proteins identified by a proteomics-based approach using cultured HUVECs may be involved not only in replicative senescence but also in functional alterations in vascular endothelial cells with senescence-associated phenotypes and may serve as molecular markers for these processes.

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Section: Discussionmentioning

confidence: 58%

Searching for Genes Involved in Arteriosclerosis: Proteomic Analysis of Cultured Human Umbilical Vein Endothelial Cells Undergoing Replicative Senescence

Kamino

Hiratsuka

Toda

et al. 2003

Cell Struct. Funct.

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“…BAT1 might be a negative regulator of inflammation, acting by downregulating the production of cytokines, including TNFα, IL1 and IL6 (Allcock et al, 2001). The human BAT1 protein has been identified as an ATP-dependent RNA helicase (Peelman et al, 1995) of the DExD/H family and is homologous to the previously described p47 protein of rat (Nair et al, 1992). Rediscovered as an essential RNA splicing factor, and sometimes renamed UAP56 in mammals (Fleckner et al, 1997), Sub2p in yeast Zhang and Green, 2001) and HEL in Drosophila (Gatfield et al, 2001), this helicase enables U2 small nuclear ribonucleoprotein (snRNP) attachment to the splicing branch point (Fleckner et al, 1997).…”

Section: Introductionmentioning

confidence: 98%

Binding of ATP to UAP56 is necessary for mRNA export

Kota

Wagner

Huerta

et al. 2008

Journal of Cell Science

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The major-histocompatibility-complex protein UAP56 (BAT1) is a DEAD-box helicase that is deposited on mRNA during splicing. UAP56 is retained on spliced mRNA in an exon junction complex (EJC) or, alternatively, with the TREX complex at the 5Ј end, where it might facilitate the export of the spliced mRNA to the cytoplasm. Using confocal microscopy, UAP56 was found to be concentrated in RNA-splicing speckled domains of nuclei but was also enriched in adjacent nuclear regions, sites at which most mRNA transcription and splicing occur. At speckled domains, UAP56 was in complexes with the RNA-splicing and -export protein SRm160, and, as measured by FRAP, was in a dynamic binding equilibrium. The application of an in vitro FRAP assay, in which fluorescent nuclear proteins are photobleached in digitonin-extracted cells, revealed that the equilibrium binding of UAP56 in complexes at speckled domains was directly regulated by ATP binding. This was confirmed using a point mutant of UAP56 that did not bind ATP. Point mutation of UAP56 to eliminate ATP binding did not affect RNA splicing, but strongly inhibited the export of mRNA to the cytoplasm. Supplementary material available online at

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“…New AR regulators include the serine/threonine kinase HIPK2 (Rinaldo et al 2007); the lipid kinase DGKI (Raben and Tu-Sekine 2008); nuclear factors PHACTR3 (also known as scapinin), which is an actin and PP1 phosphatase-binding protein associated with the nuclear scaffold (Sagara et al 2003(Sagara et al , 2009); MED19, a component of the Mediator complex (Baidoobonso et al 2007); and MXD1, which competes with MYC for binding to MAX (Wahlstrom and Henriksson 2007). Other factors identified were NUP153, subunit of the nuclear pore complex (Ball and Ullman 2005); DDX39B (also known as BAT1), an RNA helicase involved in mRNA splicing and transport (Peelman et al 1995); HLF (Hunger et al 1992) and CREB1 (Siu and Jin 2007), both bZIP transcription factors; HHEX, a homeobox transcription factor (Bedford et al 1993); and CSTF2T, a pre-mRNA binding protein (Takagaki and Manley 1997). Signaling molecules not previously linked to AR activity were also identified and include CELSR1, a nonclassical cadherin involved in cell-cell communication (Hadjantonakis et al 1997); GPR179, an orphan G-coupled protein receptor (Bjarnadottir et al 2005); RPH3A, involved in protein transport and vesicle exocytosis (Inagaki et al 1994); and MRPL40, nuclear-encoded mitochondrial ribosomal protein (Kenmochi et al 2001).…”

Section: Genome-wide Rnai Screen For New Ar Regulatorsmentioning

confidence: 99%

A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells

Imberg-Kazdan

Greenfield

et al. 2013

Genome Res.

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The androgen receptor (AR) is a mediator of both androgen-dependent and castration-resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA-approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR-negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells.

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The BAT1 gene in the MHC encodes an evolutionarily conserved putative nuclear RNA helicase of the DEAD family

Cited by 51 publications

References 33 publications

Searching for Genes Involved in Arteriosclerosis: Proteomic Analysis of Cultured Human Umbilical Vein Endothelial Cells Undergoing Replicative Senescence

Searching for Genes Involved in Arteriosclerosis: Proteomic Analysis of Cultured Human Umbilical Vein Endothelial Cells Undergoing Replicative Senescence

Binding of ATP to UAP56 is necessary for mRNA export

A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells

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