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 induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
journal_name
Genes Devjournal_title
Genes & developmentauthors
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 Jdoi
10.1101/gad.286112.116subject
Has Abstractpub_date
2016-10-01 00:00:00pages
2187-2198issue
19eissn
0890-9369issn
1549-5477pii
gad.286112.116journal_volume
30pub_type
杂志文章abstract::The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic β cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions impro...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.342378.120
更新日期:2021-01-14 00:00:00
abstract::Growth of numerous cancer types is believed to be driven by a subpopulation of poorly differentiated cells, often referred to as cancer stem cells (CSCs), that have the capacity for self-renewal, tumor initiation, and generation of nontumorigenic progeny. Despite their potentially key role in tumor establishment and m...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.188292.112
更新日期:2012-09-01 00:00:00
abstract::Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously ide...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.338061.120
更新日期:2020-08-01 00:00:00
abstract::The embryonic lethal abnormal visual system (ELAV) is a gene-specific regulator of alternative pre-mRNA processing in neurons of Drosophila. Here we define a functional in vivo binding site for ELAV in neurons through the development of a reporter gene system in transgenic animals in combination with in vitro binding ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1106703
更新日期:2003-10-15 00:00:00
abstract::Transcription factors represent one of the largest groups of proteins regulated by SUMO (small ubiquitin-like modifier) modification, and their sumoylation is usually associated with transcriptional repression. To investigate whether sumoylation plays a general role in regulating transcription in yeast, we determined ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1917910
更新日期:2010-06-15 00:00:00
abstract::A new gene, SCH9, was isolated from Saccharomyces cerevisiae by its ability to complement a cdc25ts mutation. Sequence analysis indicates that it encodes a 90,000-dalton protein with a carboxy-terminal domain homologous to yeast and mammalian cAMP-dependent protein kinase catalytic subunits. In addition to suppressing...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.2.5.517
更新日期:1988-05-01 00:00:00
abstract::During Drosophila embryogenesis, ectodermal cells of the lateral epithelium stretch in a coordinated fashion to internalize the amnioserosa cells and close the embryo dorsally. This process, dorsal closure, requires two signaling pathways: the Drosophila Jun-amino-terminal kinase (DJNK) pathway and the Dpp pathway. We...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.13.1717
更新日期:1997-07-01 00:00:00
abstract::Class Ia phosphatidylinositol 3 kinase (PI3K) is required for oncogenic receptor-mediated transformation; however, the individual roles of the two commonly expressed class Ia PI3K isoforms in oncogenic receptor signaling have not been elucidated in vivo. Here, we show that genetic ablation of p110α blocks tumor format...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.191973.112
更新日期:2012-07-15 00:00:00
abstract::In somatic cells of Xenopus, transcription of the TFIIIA gene initiates greater than 200 bp upstream from the start site used in oocytes. The resultant mRNA encodes a protein, S-TFIIIA, that is 22 amino acids longer at its amino terminus than the abundant form of TFIIIA in oocytes (O-TFIIIA). S-TFIIIA binds the 5S RNA...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.4.9.1602
更新日期:1990-09-01 00:00:00
abstract::Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.299172.117
更新日期:2017-07-15 00:00:00
abstract::Two broad gene classes are distinguished within multicellular organisms: cell type-specific genes, which confer particular cellular properties, and ubiquitous genes that support general cellular functions. However, certain so-called ubiquitous genes show functionally relevant cell type-specific repression. How such re...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.287904.116
更新日期:2016-09-15 00:00:00
abstract::In Drosophila, the development of the compound eye depends on the movement of a morphogenetic furrow (MF) from the posterior (P) to the anterior (A) of the eye imaginal disc. We define several subdomains along the A-P axis of the eye disc that express distinct combinations of transcription factors. One subdomain, ante...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1009002
更新日期:2002-09-15 00:00:00
abstract::The transcription factor TFIIB plays a central role in preinitiation complex assembly, providing a bridge between promoter-bound TFIID and RNA Polymerase II. TFIIB possesses sequence-specific DNA-binding ability and interacts with the TFIIB-recognition element (BRE), present in many promoters. Here we show that the BR...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.206901
更新日期:2001-11-15 00:00:00
abstract::The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs). Seven genes (smg-1-7, for suppressor with morphological effect on genitalia) that are essential for NMD were originally identified in the nematode Caenorhabditis elegans, and orthologs of these gene...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.417707
更新日期:2007-05-01 00:00:00
abstract::Smads regulate transcription of defined genes in response to TGF-beta receptor activation, although the mechanisms of Smad-mediated transcription are not well understood. We demonstrate that the TGF-beta-inducible Smad3 uses the tumor suppressor Smad4/DPC4 and CBP/p300 as transcriptional coactivators, which associate ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.14.2153
更新日期:1998-07-15 00:00:00
abstract::Changes in the pattern of gene expression play an important role in allowing cancer cells to acquire their hallmark characteristics, while genomic instability enables cells to acquire genetic alterations that promote oncogenesis. Chromatin plays central roles in both transcriptional regulation and the maintenance of g...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.255182.114
更新日期:2015-02-01 00:00:00
abstract::Morphogenesis of the insect kidney, the Malpighian tubules, is controlled in Drosophila by a single large cell, the tip cell. It has been postulated that this cell sends out a mitogenic signal that induces the division of neighboring cells. The signal and the molecules that receive it have remained elusive. We show th...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.12.1781
更新日期:1998-06-15 00:00:00
abstract::Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder that affects growth properties of neural-crest-derived cell populations. In addition, approximately one-half of NF1 patients exhibit learning disabilities. To characterize NF1 function both in vitro and in vivo, we circumvent the embryonic lethality of NF1...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.862101
更新日期:2001-04-01 00:00:00
abstract::Ecsit is a cytosolic adaptor protein essential for inflammatory response and embryonic development via the Toll-like and BMP (bone morphogenetic protein) signal transduction pathways, respectively. Here, we demonstrate a mitochondrial function for Ecsit (an evolutionary conserved signaling intermediate in Toll pathway...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.408407
更新日期:2007-03-01 00:00:00
abstract::We have studied the sequence requirements for 3'-end formation of rDNA transcripts in a cell-free system and show that the generation of correct ends of mouse pre-rRNA is brought about by a two-step process that involves a bona fide termination reaction, followed by a specific trimming of the primary transcript by 10 ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.3.2.224
更新日期:1989-02-01 00:00:00
abstract::Two retrovirus promoter trap vectors (U3His and U3Neo) have been used to disrupt genes expressed in totipotent murine embryonal stem (ES) cells. Selection in L-histidinol or G418 produced clones in which the coding sequences for histidinol-dehydrogenase or neomycin-phosphotransferase were fused to sequences in or near...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.6.6.919
更新日期:1992-06-01 00:00:00
abstract::Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they functi...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.220467.113
更新日期:2013-06-01 00:00:00
abstract::Members of the metazoan nuclear receptor superfamily regulate gene expression programs in response to binding of cognate lipophilic ligands. Evolutionary studies using bioinformatics tools have concluded that lower eukaryotes, such as fungi, lack nuclear receptor homologs. Here we review recent discoveries suggesting ...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.1743009
更新日期:2009-02-15 00:00:00
abstract::We have cloned four cyclin-B homologs from Saccharomyces cerevisiae, CLB1-CLB4, using the polymerase chain reaction and low stringency hybridization approaches. These genes form two classes based on sequence relatedness: CLB1 and CLB2 show highest homology to the Schizosaccharomyces pombe cyclin-B homolog cdc13 involv...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.6.11.2021
更新日期:1992-11-01 00:00:00
abstract::Sexual identity in Drosophila is determined by zygotic X-chromosome dose. Two potent indicators of X-chromosome dose are sisterless-a (sis-a) and sisterless-b (sis-b). Genetic analysis has shown that a diplo-X dose of these genes activates their regulatory target, the feminizing switch gene Sex-lethal (Sxl), whereas a...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.9.1688
更新日期:1993-09-01 00:00:00
abstract::We have investigated the DNA-binding, oligomerization, and trans-activation functions of isolated segments of murine p53. We find that p53 has two autonomous DNA-binding regions. One domain, from amino acid 280 to 390, forms stable tetramers and binds DNA nonspecifically. The biological significance, if any, of this D...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.12b.2575
更新日期:1993-12-01 00:00:00
abstract::The discovery of transcription factors (TFs) controlling pathways in health and disease is of paramount interest. We designed a widely applicable method, dubbed barcorded synthetic tandem repeat promoter screening (BC-STAR-PROM), to identify signal-activated TFs without any a priori knowledge about their properties. T...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.284828.116
更新日期:2016-08-15 00:00:00
abstract::NF-kappa B is an inducible transcription factor comprised of a 50-kD (p50) and a 65-kD (p65) subunit. Induction of NF-kappa B activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, I kappa B, followed by translocation of the active transcriptio...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.6.10.1899
更新日期:1992-10-01 00:00:00
abstract::We describe evidence that a regulatory B subunit of protein phosphatase 2A (PP2A) positively regulates an RTK-Ras-MAP kinase signaling cascade during Caenorhabditis elegans vulval induction. Although reduction of sur-6 PP2A-B function causes few vulval induction defects in an otherwise wild-type background, sur-6 PP2A...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.19.2562
更新日期:1999-10-01 00:00:00
abstract::In petunia flowers, the loci an1, an2, and an11 control the pigmentation of the flower by stimulating the transcription of anthocyanin biosynthetic genes. The an1 and an2 locus were recently cloned and encode a basic helix-loop-helix (bHLH) and MYB-domain transcriptional activator, respectively. Here, we report the is...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.11.1422
更新日期:1997-06-01 00:00:00