Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells
High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-H...
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| Veröffentlicht in: | Cancers 2021-01, Vol.13 (3), p.489 |
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| creator | James, Claire D Saini, Siddharth Sesay, Fatmata Ko, Kevin Felthousen-Rusbasan, Jessica Iness, Audra N Nulton, Tara Windle, Brad Dozmorov, Mikhail G Morgan, Iain M Litovchick, Larisa |
| description | High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers. |
| doi_str_mv | 10.3390/cancers13030489 |
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In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13030489</identifier><identifier>PMID: 33513914</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Cancer ; Cell cycle ; Cell proliferation ; Cervical cancer ; Competition ; Dimerization ; E2F protein ; Gene expression ; Genomes ; Head & neck cancer ; Head and neck carcinoma ; Human papillomavirus ; Keratinocytes ; Kinases ; Papillomaviridae ; Proteins ; Retina ; Retinoblastoma ; Retinoblastoma protein ; Transcription ; Tumorigenesis ; Tumors</subject><ispartof>Cancers, 2021-01, Vol.13 (3), p.489</ispartof><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-efbb8194c41c6ecfe5a822ddeb6df399e40be0d8ae06af946a553aa08e0efa853</citedby><cites>FETCH-LOGICAL-c421t-efbb8194c41c6ecfe5a822ddeb6df399e40be0d8ae06af946a553aa08e0efa853</cites><orcidid>0000-0002-9973-3639 ; 0000-0002-0086-8358 ; 0000-0001-5194-1319 ; 0000-0002-9540-597X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866234/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866234/$$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/33513914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>James, Claire D</creatorcontrib><creatorcontrib>Saini, Siddharth</creatorcontrib><creatorcontrib>Sesay, Fatmata</creatorcontrib><creatorcontrib>Ko, Kevin</creatorcontrib><creatorcontrib>Felthousen-Rusbasan, Jessica</creatorcontrib><creatorcontrib>Iness, Audra N</creatorcontrib><creatorcontrib>Nulton, Tara</creatorcontrib><creatorcontrib>Windle, Brad</creatorcontrib><creatorcontrib>Dozmorov, Mikhail G</creatorcontrib><creatorcontrib>Morgan, Iain M</creatorcontrib><creatorcontrib>Litovchick, Larisa</creatorcontrib><title>Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers.</description><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell proliferation</subject><subject>Cervical cancer</subject><subject>Competition</subject><subject>Dimerization</subject><subject>E2F protein</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Head & neck cancer</subject><subject>Head and neck carcinoma</subject><subject>Human papillomavirus</subject><subject>Keratinocytes</subject><subject>Kinases</subject><subject>Papillomaviridae</subject><subject>Proteins</subject><subject>Retina</subject><subject>Retinoblastoma</subject><subject>Retinoblastoma protein</subject><subject>Transcription</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkd1rFDEUxYMottQ--yYBX3wZm8zNZJMXoazVLVRcFvVJCJnMzW7qTLImM0X_e6ef1N6XXDi_HHJyCHnN2XsAzU6cjQ5z4cCACaWfkcOaLepKSi2eP9oPyHEpl2weAL6Qi5fkAKDhoLk4JD83WMaUQ9zScYf04-bs9AtdpmHf4x96HnehDWO5kdY59cFjtmNIkSZPV2G7qzah_KKr9Q-6TiWM4QrpahpspEvs-_KKvPC2L3h8dx6R75_Ovi1X1cXXz-fL04vKiZqPFfq2VVwLJ7iT6Dw2VtV112ErOw9ao2Atsk5ZZNJ6LaRtGrCWKWTorWrgiHy49d1P7YCdwzhm25t9DoPNf02ywfyvxLAz23RlFkrKGsRs8O7OIKff0_wjZgjFzRFsxDQVUwsFioMCOaNvn6CXacpxjndNCeBMg56pk1vK5VRKRv_wGM7MdXnmSXnzjTePMzzw91XBPyXkl4Q</recordid><startdate>20210127</startdate><enddate>20210127</enddate><creator>James, Claire D</creator><creator>Saini, Siddharth</creator><creator>Sesay, Fatmata</creator><creator>Ko, Kevin</creator><creator>Felthousen-Rusbasan, Jessica</creator><creator>Iness, Audra N</creator><creator>Nulton, Tara</creator><creator>Windle, Brad</creator><creator>Dozmorov, Mikhail G</creator><creator>Morgan, Iain M</creator><creator>Litovchick, Larisa</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9973-3639</orcidid><orcidid>https://orcid.org/0000-0002-0086-8358</orcidid><orcidid>https://orcid.org/0000-0001-5194-1319</orcidid><orcidid>https://orcid.org/0000-0002-9540-597X</orcidid></search><sort><creationdate>20210127</creationdate><title>Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells</title><author>James, Claire D ; 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In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33513914</pmid><doi>10.3390/cancers13030489</doi><orcidid>https://orcid.org/0000-0002-9973-3639</orcidid><orcidid>https://orcid.org/0000-0002-0086-8358</orcidid><orcidid>https://orcid.org/0000-0001-5194-1319</orcidid><orcidid>https://orcid.org/0000-0002-9540-597X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Cancer Cell cycle Cell proliferation Cervical cancer Competition Dimerization E2F protein Gene expression Genomes Head & neck cancer Head and neck carcinoma Human papillomavirus Keratinocytes Kinases Papillomaviridae Proteins Retina Retinoblastoma Retinoblastoma protein Transcription Tumorigenesis Tumors |
| title | Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells |
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