Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors

We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated b...

Full description

Saved in:
Bibliographic Details
Published in:Genes & development 2013-10, Vol.27 (20), p.2221-2226
Main Authors: Wajapeyee, Narendra, Malonia, Sunil K, Palakurthy, Rajendra K, Green, Michael R
Format: Article
Language:English
Subjects:
Animals
DNA Methylation
Epigenesis, Genetic
fas Receptor - genetics
fas Receptor - metabolism
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor
Mice
Models, Biological
NIH 3T3 Cells
Protein Binding
ras Proteins - genetics
ras Proteins - metabolism
Research Communication
RNA Interference
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53
cites cdi_FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53
container_end_page 2226
container_issue 20
container_start_page 2221
container_title Genes & development
container_volume 27
creator Wajapeyee, Narendra
Malonia, Sunil K
Palakurthy, Rajendra K
Green, Michael R
description We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.
doi_str_mv 10.1101/gad.227413.113
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3814642</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1443998678</sourcerecordid><originalsourceid>FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53</originalsourceid><addsrcrecordid>eNqNkUtr3DAUhUVpaaaTbrMMWnbjqWS97E0ghPQBgUDbrIUsSx4FW3J07UL_fTWdaUh3XUmX-53DuRyELijZUUrox8H0u7pWnLIys1doQwVvK8GVeo02pGlJ1TLZnqF3AI-EEEmkfIvOak6JUJxtENxHmwYXg8Xfrr_jPmRnF8AQRhdtiANOHi_rlDKGdZ6zAyjfwjvAyz6nddjjlHuXXY-LMq9hmVxc_qiyiWBzmJeQohnL-iSHc_TGmxHc-9O7RQ-fbn_cfKnu7j9_vbm-qyyv2VI1je2oF8arznTeMkmZc76VUnEjal93jVRKcsOp56oRktO-6aVQpHaslZ1gW3R19J3XbnK9LcGyGfWcw2TyL51M0P9uYtjrIf3UrKFclgxb9OFkkNPT6mDRUwDrxtFEl1bQB0pQzhn7D5Szti2Jm4LujqjNCSA7_5yIEn0oVZdS9bHUMh-8L1_e8Yz_bZH9BtHxoMo</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1443998678</pqid></control><display><type>article</type><title>Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors</title><source>Freely Accessible Science Journals - check A-Z of ejournals</source><source>PubMed Central</source><creator>Wajapeyee, Narendra ; Malonia, Sunil K ; Palakurthy, Rajendra K ; Green, Michael R</creator><creatorcontrib>Wajapeyee, Narendra ; Malonia, Sunil K ; Palakurthy, Rajendra K ; Green, Michael R</creatorcontrib><description>We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.227413.113</identifier><identifier>PMID: 24105743</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Animals ; DNA Methylation ; Epigenesis, Genetic ; fas Receptor - genetics ; fas Receptor - metabolism ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genes, Tumor Suppressor ; Mice ; Models, Biological ; NIH 3T3 Cells ; Protein Binding ; ras Proteins - genetics ; ras Proteins - metabolism ; Research Communication ; RNA Interference ; Signal Transduction</subject><ispartof>Genes &amp; development, 2013-10, Vol.27 (20), p.2221-2226</ispartof><rights>2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53</citedby><cites>FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814642/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814642/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24105743$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wajapeyee, Narendra</creatorcontrib><creatorcontrib>Malonia, Sunil K</creatorcontrib><creatorcontrib>Palakurthy, Rajendra K</creatorcontrib><creatorcontrib>Green, Michael R</creatorcontrib><title>Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors</title><title>Genes &amp; development</title><addtitle>Genes Dev</addtitle><description>We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.</description><subject>Animals</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>fas Receptor - genetics</subject><subject>fas Receptor - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Silencing</subject><subject>Genes, Tumor Suppressor</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>NIH 3T3 Cells</subject><subject>Protein Binding</subject><subject>ras Proteins - genetics</subject><subject>ras Proteins - metabolism</subject><subject>Research Communication</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNqNkUtr3DAUhUVpaaaTbrMMWnbjqWS97E0ghPQBgUDbrIUsSx4FW3J07UL_fTWdaUh3XUmX-53DuRyELijZUUrox8H0u7pWnLIys1doQwVvK8GVeo02pGlJ1TLZnqF3AI-EEEmkfIvOak6JUJxtENxHmwYXg8Xfrr_jPmRnF8AQRhdtiANOHi_rlDKGdZ6zAyjfwjvAyz6nddjjlHuXXY-LMq9hmVxc_qiyiWBzmJeQohnL-iSHc_TGmxHc-9O7RQ-fbn_cfKnu7j9_vbm-qyyv2VI1je2oF8arznTeMkmZc76VUnEjal93jVRKcsOp56oRktO-6aVQpHaslZ1gW3R19J3XbnK9LcGyGfWcw2TyL51M0P9uYtjrIf3UrKFclgxb9OFkkNPT6mDRUwDrxtFEl1bQB0pQzhn7D5Szti2Jm4LujqjNCSA7_5yIEn0oVZdS9bHUMh-8L1_e8Yz_bZH9BtHxoMo</recordid><startdate>20131015</startdate><enddate>20131015</enddate><creator>Wajapeyee, Narendra</creator><creator>Malonia, Sunil K</creator><creator>Palakurthy, Rajendra K</creator><creator>Green, Michael R</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20131015</creationdate><title>Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors</title><author>Wajapeyee, Narendra ; Malonia, Sunil K ; Palakurthy, Rajendra K ; Green, Michael R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>DNA Methylation</topic><topic>Epigenesis, Genetic</topic><topic>fas Receptor - genetics</topic><topic>fas Receptor - metabolism</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Silencing</topic><topic>Genes, Tumor Suppressor</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>NIH 3T3 Cells</topic><topic>Protein Binding</topic><topic>ras Proteins - genetics</topic><topic>ras Proteins - metabolism</topic><topic>Research Communication</topic><topic>RNA Interference</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wajapeyee, Narendra</creatorcontrib><creatorcontrib>Malonia, Sunil K</creatorcontrib><creatorcontrib>Palakurthy, Rajendra K</creatorcontrib><creatorcontrib>Green, Michael R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes &amp; development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wajapeyee, Narendra</au><au>Malonia, Sunil K</au><au>Palakurthy, Rajendra K</au><au>Green, Michael R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors</atitle><jtitle>Genes &amp; development</jtitle><addtitle>Genes Dev</addtitle><date>2013-10-15</date><risdate>2013</risdate><volume>27</volume><issue>20</issue><spage>2221</spage><epage>2226</epage><pages>2221-2226</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>24105743</pmid><doi>10.1101/gad.227413.113</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0890-9369
ispartof Genes & development, 2013-10, Vol.27 (20), p.2221-2226
issn 0890-9369
1549-5477
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3814642
source Freely Accessible Science Journals - check A-Z of ejournals; PubMed Central
subjects Animals
DNA Methylation
Epigenesis, Genetic
fas Receptor - genetics
fas Receptor - metabolism
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor
Mice
Models, Biological
NIH 3T3 Cells
Protein Binding
ras Proteins - genetics
ras Proteins - metabolism
Research Communication
RNA Interference
Signal Transduction
title Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T17%3A49%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oncogenic%20RAS%20directs%20silencing%20of%20tumor%20suppressor%20genes%20through%20ordered%20recruitment%20of%20transcriptional%20repressors&rft.jtitle=Genes%20&%20development&rft.au=Wajapeyee,%20Narendra&rft.date=2013-10-15&rft.volume=27&rft.issue=20&rft.spage=2221&rft.epage=2226&rft.pages=2221-2226&rft.issn=0890-9369&rft.eissn=1549-5477&rft_id=info:doi/10.1101/gad.227413.113&rft_dat=%3Cproquest_pubme%3E1443998678%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c423t-88cb1f5af7babfc3613eef96674a52f2b867764a41f4785641d8d65702e396b53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1443998678&rft_id=info:pmid/24105743&rfr_iscdi=true