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NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways
Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB sub...
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Published in: | PLoS genetics 2020-06, Vol.16 (6), p.e1008863-e1008863 |
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description | Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling. |
doi_str_mv | 10.1371/journal.pgen.1008863 |
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In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1008863</identifier><identifier>PMID: 32559195</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Acetyltransferase ; Apoptosis ; Biology and Life Sciences ; Cell adhesion & migration ; Cell cycle ; Cell death ; Cell growth ; Cell proliferation ; Cell survival ; Cellular signal transduction ; Cloning ; DNA damage ; Drosophila ; Epidermal growth factor receptors ; Genetic aspects ; Genetic regulation ; Genetic screening ; Grb2 protein ; Insects ; MAP kinase ; Medical research ; Medicine and Health Sciences ; Metabolism ; Mutants ; Mutation ; N-terminal acetyltransferase ; Observations ; Physiological aspects ; Post-transcription ; Research and Analysis Methods ; Signal transduction ; Therapeutic applications ; Tumor suppressor genes ; Ubiquitin ; Ubiquitin-protein ligase</subject><ispartof>PLoS genetics, 2020-06, Vol.16 (6), p.e1008863-e1008863</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Sheng, Du. 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In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling.</description><subject>Acetyltransferase</subject><subject>Apoptosis</subject><subject>Biology and Life Sciences</subject><subject>Cell adhesion & migration</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell survival</subject><subject>Cellular signal transduction</subject><subject>Cloning</subject><subject>DNA damage</subject><subject>Drosophila</subject><subject>Epidermal growth factor receptors</subject><subject>Genetic aspects</subject><subject>Genetic regulation</subject><subject>Genetic screening</subject><subject>Grb2 protein</subject><subject>Insects</subject><subject>MAP kinase</subject><subject>Medical research</subject><subject>Medicine and Health 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regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways</title><author>Sheng, Zhentao ; Du, Wei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c773t-d163a15dfa16f73d1efe6f2e1cd12580483ad82cb5560ad6e152daeaf4b316593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetyltransferase</topic><topic>Apoptosis</topic><topic>Biology and Life Sciences</topic><topic>Cell adhesion & migration</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell growth</topic><topic>Cell proliferation</topic><topic>Cell survival</topic><topic>Cellular signal transduction</topic><topic>Cloning</topic><topic>DNA damage</topic><topic>Drosophila</topic><topic>Epidermal growth factor receptors</topic><topic>Genetic aspects</topic><topic>Genetic regulation</topic><topic>Genetic screening</topic><topic>Grb2 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genetics</jtitle><date>2020-06-19</date><risdate>2020</risdate><volume>16</volume><issue>6</issue><spage>e1008863</spage><epage>e1008863</epage><pages>e1008863-e1008863</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. 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subjects | Acetyltransferase Apoptosis Biology and Life Sciences Cell adhesion & migration Cell cycle Cell death Cell growth Cell proliferation Cell survival Cellular signal transduction Cloning DNA damage Drosophila Epidermal growth factor receptors Genetic aspects Genetic regulation Genetic screening Grb2 protein Insects MAP kinase Medical research Medicine and Health Sciences Metabolism Mutants Mutation N-terminal acetyltransferase Observations Physiological aspects Post-transcription Research and Analysis Methods Signal transduction Therapeutic applications Tumor suppressor genes Ubiquitin Ubiquitin-protein ligase |
title | NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways |
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