Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation.

Abstract:

:Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.

journal_name

Genes Dev

journal_title

Genes & development

authors

Roy N,Malik S,Villanueva KE,Urano A,Lu X,Von Figura G,Seeley ES,Dawson DW,Collisson EA,Hebrok M

doi

10.1101/gad.256628.114

subject

Has Abstract

pub_date

2015-03-15 00:00:00

pages

658-71

issue

6

eissn

0890-9369

issn

1549-5477

pii

29/6/658

journal_volume

29

pub_type

杂志文章
  • sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins.

    abstract::Mutations that influence lin-12 activity in Caenorhabditis elegans may identify conserved factors that regulate the activity of lin-12/Notch proteins. We describe genetic evidence indicating that sel-10 is a negative regulator of lin-12/Notch-mediated signaling in C. elegans. Sequence analysis shows that SEL-10 is a m...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.11.23.3182

    authors: Hubbard EJ,Wu G,Kitajewski J,Greenwald I

    更新日期:1997-12-01 00:00:00

  • PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes.

    abstract::PBAF and BAF are two chromatin-remodeling complexes of the SWI/SNF family essential for mammalian transcription and development. Although these complexes share eight identical subunits, only PBAF can facilitate transcriptional activation by nuclear receptors in vitro. Here we show that these complexes have selectivity...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1323805

    authors: Yan Z,Cui K,Murray DM,Ling C,Xue Y,Gerstein A,Parsons R,Zhao K,Wang W

    更新日期:2005-07-15 00:00:00

  • Genomic instability and endoreduplication triggered by RAD17 deletion.

    abstract::Cell cycle checkpoints are critical for genomic stability. Rad17, a component of the checkpoint clamp loader complex (Rad17/Rfc2-5), is required for the response to DNA damage and replication stress. To explore the role of Rad17 in the maintenance of genomic integrity, we established somatic conditional alleles of RAD...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1065103

    authors: Wang X,Zou L,Zheng H,Wei Q,Elledge SJ,Li L

    更新日期:2003-04-15 00:00:00

  • MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development.

    abstract::Alternative pre-mRNA splicing determines many changes in gene expression during development. Two regulators known to control splicing patterns during neuron and muscle differentiation are the polypyrimidine tract-binding protein (PTB) and its neuronal homolog nPTB. These proteins repress certain exons in early myoblas...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1500707

    authors: Boutz PL,Chawla G,Stoilov P,Black DL

    更新日期:2007-01-01 00:00:00

  • Suppression of a cold-sensitive mutation in 16S rRNA by overexpression of a novel ribosome-binding factor, RbfA.

    abstract::A novel 15-kDa protein, RbfA, has been identified by virtue of its ability to act as a high copy suppressor of a previously characterized dominant cold-sensitive mutation (C23U) in 16S rRNA. RbfA is found associated with free 30S ribosomal subunits, but not with 70S ribosomes or polysomes, and is essential for maximal...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.9.5.626

    authors: Dammel CS,Noller HF

    更新日期:1995-03-01 00:00:00

  • SAS-mediated acetylation of histone H4 Lys 16 is required for H2A.Z incorporation at subtelomeric regions in Saccharomyces cerevisiae.

    abstract::The yeast SAS (Something About Silencing) complex and the histone variant H2A.Z have both previously been linked to an antisilencing function at the subtelomeric regions. SAS is an H4 Lys 16-specific histone acetyltransferase complex. Here we demonstrate that the H4 Lys 16 acetylation by SAS is required for efficient ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1439206

    authors: Shia WJ,Li B,Workman JL

    更新日期:2006-09-15 00:00:00

  • Regulating the regulator: an RNA decoy acts as an OFF switch for the regulation of an sRNA.

    abstract::Many bacterial small regulatory RNAs (sRNAs) pair with mRNA targets, stimulating or inhibiting mRNA stability and/or translation. Regulation of these sRNAs is usually due to tight transcriptional regulation of synthesis.In this issue of Genes & Development and a related paper in Molecular Microbiology, Figueroa-Bossi ...

    journal_title:Genes & development

    pub_type: 评论,杂志文章

    doi:10.1101/gad.1846609

    authors: Mandin P,Gottesman S

    更新日期:2009-09-01 00:00:00

  • SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.

    abstract::Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.286112.116

    authors: Tordella L,Khan S,Hohmeyer A,Banito A,Klotz S,Raguz S,Martin N,Dhamarlingam G,Carroll T,González Meljem JM,Deswal S,Martínez-Barbera JP,García-Escudero R,Zuber J,Zender L,Gil J

    更新日期:2016-10-01 00:00:00

  • Analysis of the lethal interaction between the prune and Killer of prune mutations of Drosophila.

    abstract::The third-chromosome mutation Killer of prune (K-pn) causes no phenotype by itself, but causes lethality in individuals homozygous for the nonlethal X-chromosome mutation prune (pn). We have recovered 12 gamma-ray-induced revertants of Killer of prune. All of the revertants fail to complement a recessive cell lethal m...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.2.10.1333

    authors: Biggs J,Tripoulas N,Hersperger E,Dearolf C,Shearn A

    更新日期:1988-10-01 00:00:00

  • Structures of three distinct activator-TFIID complexes.

    abstract::Sequence-specific DNA-binding activators, key regulators of gene expression, stimulate transcription in part by targeting the core promoter recognition TFIID complex and aiding in its recruitment to promoter DNA. Although it has been established that activators can interact with multiple components of TFIID, it is unk...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1790709

    authors: Liu WL,Coleman RA,Ma E,Grob P,Yang JL,Zhang Y,Dailey G,Nogales E,Tjian R

    更新日期:2009-07-01 00:00:00

  • CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons.

    abstract::Serotonin is a bioamine regulating bone mass accrual differently depending on its site of synthesis. It decreases accrual when synthesized in the gut, and increases it when synthesized in the brain. The signal transduction events elicited by gut-derived serotonin once it binds to the Htr1b receptor present on osteobla...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1977210

    authors: Oury F,Yadav VK,Wang Y,Zhou B,Liu XS,Guo XE,Tecott LH,Schutz G,Means AR,Karsenty G

    更新日期:2010-10-15 00:00:00

  • A unique zinc finger protein is associated preferentially with active ecdysone-responsive loci in Drosophila.

    abstract::Using an immunochemical approach, we have identified a unique antigen, PEP (protein on ecdysone puffs), which is associated in third-instar larvae with the active ecdysone-regulated loci on polytene chromosomes; PEP is not associated with most intermolt puffs and is found on some, but not all, heat shock-induced puffs...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.5.2.188

    authors: Amero SA,Elgin SC,Beyer AL

    更新日期:1991-02-01 00:00:00

  • The transcription of Xenopus laevis embryonic U1 snRNA genes changes when oocytes mature into eggs.

    abstract::X. laevis stage VI oocytes respond differently from unfertilized eggs when injected with the genes for X. laevis embryonic U1 RNAs, xU1b1, and xU1b2. Upon maturation of oocytes into eggs, the efficiency of transcription decreases greatly and the ratio of xU1b1 to xU1b2 RNA transcription changes. Moreover, DNA replicat...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1.1.47

    authors: Lund E,Bostock CJ,Dahlberg JE

    更新日期:1987-03-01 00:00:00

  • Sex-specific regulation of the male-specific lethal-1 dosage compensation gene in Drosophila.

    abstract::Dosage compensation in Drosophila occurs by a twofold increase in transcription per copy of X-linked genes in males (XY) compared with females (XX). msl-1 is one of four genes that are essential for dosage compensation in males, and MSL-1 protein is associated specifically with the male X chromosome. To explore the ba...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.8.6.698

    authors: Palmer MJ,Richman R,Richter L,Kuroda MI

    更新日期:1994-03-15 00:00:00

  • Zebrafish genetics gets the Scube on Hedgehog secretion.

    abstract::Inspired by a zebrafish mutation, two recent studies by Creanga and colleagues (pp. 1312-1325) and Tukachinsky and colleagues have shed new light on the way in which lipidated Hedgehog proteins are secreted and released from expressing cells, suggesting a model for the sequential action of the Disp and Scube2 proteins...

    journal_title:Genes & development

    pub_type: 评论,杂志文章

    doi:10.1101/gad.207126.112

    authors: Ingham PW

    更新日期:2012-11-15 00:00:00

  • Stages in the second reaction of pre-mRNA splicing: the final step is ATP independent.

    abstract::We have analyzed pre-mRNA splicing in yeast extracts immunodepleted of the PRP18 protein. We find that while the first step of splicing (cleavage at the 5' splice site, and generation of the exon 1 and lariat intermediates) is unaffected by the absence of PRP18, the second step of splicing (excision of the lariat intr...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.7.2.320

    authors: Horowitz DS,Abelson J

    更新日期:1993-02-01 00:00:00

  • Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase.

    abstract::Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.304261.117

    authors: Zhang S,Fan G,Hao Y,Hammell M,Wilkinson JE,Tonks NK

    更新日期:2017-10-01 00:00:00

  • mRNA-type introns in U6 small nuclear RNA genes: implications for the catalysis in pre-mRNA splicing.

    abstract::U6 small nuclear RNA is one of the spliceosomal RNAs involved in pre-mRNA splicing. In the fission yeast Schizosaccharomyces pombe, the U6 RNA gene was found to have an intron similar to a nuclear pre-mRNA intron, and it was proposed that the U6 intron might be inserted erroneously during pre-mRNA splicing. Using the ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.5.6.1022

    authors: Tani T,Ohshima Y

    更新日期:1991-06-01 00:00:00

  • Snail blocks the cell cycle and confers resistance to cell death.

    abstract::The Snail zinc-finger transcription factors trigger epithelial-mesenchymal transitions (EMTs), endowing epithelial cells with migratory and invasive properties during both embryonic development and tumor progression. During EMT, Snail provokes the loss of epithelial markers, as well as changes in cell shape and the ex...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.294104

    authors: Vega S,Morales AV,Ocaña OH,Valdés F,Fabregat I,Nieto MA

    更新日期:2004-05-15 00:00:00

  • CHD4/Mi-2beta activity is required for the positioning of the mesoderm/neuroectoderm boundary in Xenopus.

    abstract::Experiments in Xenopus have illustrated the importance of extracellular morphogens for embryonic gene regulation in vertebrates. Much less is known about how induction leads to the correct positioning of boundaries; for example, between germ layers. Here we report that the neuroectoderm/mesoderm boundary is controlled...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.409507

    authors: Linder B,Mentele E,Mansperger K,Straub T,Kremmer E,Rupp RA

    更新日期:2007-04-15 00:00:00

  • Novel role for a bacterial nucleoid protein in translation of mRNAs with suboptimal ribosome-binding sites.

    abstract::In Escherichia coli, the major nucleoid protein H-NS limits transcription by acting as a repressor or transcriptional silencer, presumably by its ability to close the looped chromosome domains in the nucleoid through DNA-protein-DNA bridging. Here, we demonstrate the direct involvement of H-NS as a positive factor sti...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.576310

    authors: Park HS,Ostberg Y,Johansson J,Wagner EG,Uhlin BE

    更新日期:2010-07-01 00:00:00

  • Activity and tissue-specific expression of the transcription factor NF-E1 multigene family.

    abstract::NF-E1, a DNA-binding protein that recognizes the general consensus motif WGATAR, is the first tissue-specific factor to be identified in erythroid cells. Using a probe from the murine GF-1 (NF-E1) cDNA clone, we isolated three homologous chicken cDNAs: One of these corresponds to an mRNA (NF-E1a) that is abundantly an...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.4.10.1650

    authors: Yamamoto M,Ko LJ,Leonard MW,Beug H,Orkin SH,Engel JD

    更新日期:1990-10-01 00:00:00

  • Cap-independent translation of encephalomyocarditis virus RNA: structural elements of the internal ribosomal entry site and involvement of a cellular 57-kD RNA-binding protein.

    abstract::Translation of encephalomyocarditis virus (EMCV) mRNA occurs by ribosomal internal entry into the 5'-nontranslated region (5' NTR) rather than by ribosomal scanning. The internal ribosomal entry site (IRES) in the EMCV 5' NTR was determined by in vitro translation with RNAs that were generated by in vitro transcriptio...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.4.9.1560

    authors: Jang SK,Wimmer E

    更新日期:1990-09-01 00:00:00

  • Uniform gene expression in embryos is achieved by temporal averaging of transcription noise.

    abstract::Transcription is often stochastic. This is seemingly incompatible with the importance of gene expression during development. Here we show that during zebrafish embryogenesis, transcription activation is stochastic due to (1) genes acquiring transcriptional competence at different times in different cells, (2) differen...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.302935.117

    authors: Stapel LC,Zechner C,Vastenhouw NL

    更新日期:2017-08-15 00:00:00

  • canoe encodes a novel protein containing a GLGF/DHR motif and functions with Notch and scabrous in common developmental pathways in Drosophila.

    abstract::The canoemisty1 (cnomis1) mutation was isolated by virtue of its severe rough eye phenotype from approximately 500 fly lines, each harboring a single autosomal insertion of a P element (Bm delta w). Excision of the P element generated a lethal, null allele, cnomis10, together with many revertants with normal eye morph...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.9.5.612

    authors: Miyamoto H,Nihonmatsu I,Kondo S,Ueda R,Togashi S,Hirata K,Ikegami Y,Yamamoto D

    更新日期:1995-03-01 00:00:00

  • Spatial arrangement of an RNA zipcode identifies mRNAs under post-transcriptional control.

    abstract::How RNA-binding proteins recognize specific sets of target mRNAs remains poorly understood because current approaches depend primarily on sequence information. In this study, we demonstrate that specific recognition of messenger RNAs (mRNAs) by RNA-binding proteins requires the correct spatial positioning of these seq...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.177428.111

    authors: Patel VL,Mitra S,Harris R,Buxbaum AR,Lionnet T,Brenowitz M,Girvin M,Levy M,Almo SC,Singer RH,Chao JA

    更新日期:2012-01-01 00:00:00

  • Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis.

    abstract::We describe here a new murine homeo box gene, denoted Hlx, which is expressed within specific hematopoietic lineages. The cDNA sequence indicates that Hlx differs markedly from known vertebrate homeo box genes, and linkage analysis of an interspecific murine backcross showed that it resides at a novel homeo box locus ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.5.4.509

    authors: Allen JD,Lints T,Jenkins NA,Copeland NG,Strasser A,Harvey RP,Adams JM

    更新日期:1991-04-01 00:00:00

  • Evolution of a transcriptional regulator from a transmembrane nucleoporin.

    abstract::Nuclear pore complexes (NPCs) emerged as nuclear transport channels in eukaryotic cells ∼1.5 billion years ago. While the primary role of NPCs is to regulate nucleo-cytoplasmic transport, recent research suggests that certain NPC proteins have additionally acquired the role of affecting gene expression at the nuclear ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.280941.116

    authors: Franks TM,Benner C,Narvaiza I,Marchetto MC,Young JM,Malik HS,Gage FH,Hetzer MW

    更新日期:2016-05-15 00:00:00

  • Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes.

    abstract::Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has rem...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.246538.114

    authors: Lykke-Andersen S,Chen Y,Ardal BR,Lilje B,Waage J,Sandelin A,Jensen TH

    更新日期:2014-11-15 00:00:00

  • Specific regulation of Xenopus chromosomal 5S rRNA gene transcription in vivo by histone H1.

    abstract::The incorporation of histone H1 into chromatin during embryogenesis directs the specific repression of the Xenopus oocyte 5S rRNA genes. An increase in histone H1 content specifically restricts TFIIIA-activated transcription, and a decrease in histone H1 within chromatin facilitates the activation of the oocyte 5S rRN...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.8.10.1147

    authors: Bouvet P,Dimitrov S,Wolffe AP

    更新日期:1994-05-15 00:00:00