HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53
E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export...
Gespeichert in:
| Veröffentlicht in: | Cell death and differentiation 2020-09, Vol.27 (9), p.2537-2551 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2551 |
|---|---|
| container_issue | 9 |
| container_start_page | 2537 |
| container_title | Cell death and differentiation |
| container_volume | 27 |
| creator | Yi, Sang Ah Lee, Dong Hoon Kim, Go Woon Ryu, Hyun-Wook Park, Jong Woo Lee, Jaecheol Han, Jihoon Park, Jee Hun Oh, Hwamok Lee, Jieun Choi, Junjeong Kim, Hyun-Soo Kang, Hyeok Gu Kim, Da-Hyun Chun, Kyung-Hee You, Jueng Soo Han, Jeung-Whan Kwon, So Hee |
| description | E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of
UBE2L3
which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of
UBE2L3
by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ. |
| doi_str_mv | 10.1038/s41418-020-0520-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7429875</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2382643488</sourcerecordid><originalsourceid>FETCH-LOGICAL-c498t-29a4766c0826a0c6fdc6f683eb5523d6a06e1ade23675cad7c83d41fe50e5aca3</originalsourceid><addsrcrecordid>eNp9kctuFDEQRS0EIiHwAWyQJTZsmvht9wYJRYRBipQsAhsWlseuHhz12IPdPZDvyn_wTXg0ITyksPBDrlPXt3QRek7Ja0q4Oa6CCmo6wkhHZNvkA3RIhVadFIQ_bHcuSdcToQ_Qk1qvCCFK9-oxOuCMEU41O0SfFxefujWE6CYIOM1-BFcwfN_kMuE84MUF_XGDQ4lbqNhD2UbvRjzN61ziChLUWPHyGof8LRVYzaObYk67xo3kT9GjwY0Vnt2eR-jj6bvLk0V3dv7-w8nbs86L3kwd613zrDwxTDni1RDaUobDUkrGQ3tTQF0AxpWW3gXtDQ-CDiAJSOcdP0Jv9rqbedlG8ZCm4ka7KXHtyrXNLtq_Kyl-sau8tVqw3mjZBF7dCpT8dYY62XWsHsbRJchztYw3a4ILYxr68h_0Ks8ltfEsE1qSxvTy_xQXgihqeKPonvIl11pguLNMid0FbPcB2xaw3QVsd8ov_pz1ruNXog1ge6C2UlpB-f31_ao_AYXdsVw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2434406183</pqid></control><display><type>article</type><title>HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SpringerLink Journals - AutoHoldings</source><creator>Yi, Sang Ah ; Lee, Dong Hoon ; Kim, Go Woon ; Ryu, Hyun-Wook ; Park, Jong Woo ; Lee, Jaecheol ; Han, Jihoon ; Park, Jee Hun ; Oh, Hwamok ; Lee, Jieun ; Choi, Junjeong ; Kim, Hyun-Soo ; Kang, Hyeok Gu ; Kim, Da-Hyun ; Chun, Kyung-Hee ; You, Jueng Soo ; Han, Jeung-Whan ; Kwon, So Hee</creator><creatorcontrib>Yi, Sang Ah ; Lee, Dong Hoon ; Kim, Go Woon ; Ryu, Hyun-Wook ; Park, Jong Woo ; Lee, Jaecheol ; Han, Jihoon ; Park, Jee Hun ; Oh, Hwamok ; Lee, Jieun ; Choi, Junjeong ; Kim, Hyun-Soo ; Kang, Hyeok Gu ; Kim, Da-Hyun ; Chun, Kyung-Hee ; You, Jueng Soo ; Han, Jeung-Whan ; Kwon, So Hee</creatorcontrib><description>E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of
UBE2L3
which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of
UBE2L3
by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-020-0520-5</identifier><identifier>PMID: 32203172</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/39 ; 38/89 ; 631/337/176 ; 64/60 ; 692/699/67/1244 ; 82/51 ; 82/80 ; Active Transport, Cell Nucleus ; Animals ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Carcinogenesis - genetics ; Carcinogenesis - pathology ; Cell Biology ; Cell Cycle Analysis ; Cell Line, Tumor ; Cell Nucleus - metabolism ; Cervical cancer ; Cervix ; Chromosomal Proteins, Non-Histone - metabolism ; Cytoplasm ; Degradation ; Down-Regulation - genetics ; Doxycycline - pharmacology ; E6 protein ; Exportin 1 Protein ; Female ; Gene Expression Regulation, Neoplastic ; Heterochromatin ; Human papillomavirus ; Karyopherins - metabolism ; Life Sciences ; Mice, Inbred BALB C ; Mice, Nude ; Models, Biological ; Nuclear transport ; Oncogene Proteins, Viral - metabolism ; p53 Protein ; Proteasomes ; Protein Isoforms - metabolism ; Protein transport ; Proteins ; Proteolysis ; Receptors, Cytoplasmic and Nuclear - metabolism ; Repressor Proteins - metabolism ; Risk Factors ; Stem Cells ; Transcription ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumorigenesis ; Ubiquitin-Conjugating Enzymes - genetics ; Ubiquitin-Conjugating Enzymes - metabolism ; Ubiquitination ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - pathology</subject><ispartof>Cell death and differentiation, 2020-09, Vol.27 (9), p.2537-2551</ispartof><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020</rights><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-29a4766c0826a0c6fdc6f683eb5523d6a06e1ade23675cad7c83d41fe50e5aca3</citedby><cites>FETCH-LOGICAL-c498t-29a4766c0826a0c6fdc6f683eb5523d6a06e1ade23675cad7c83d41fe50e5aca3</cites><orcidid>0000-0002-3187-6844</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/PMC7429875/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429875/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,41487,42556,51318,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32203172$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yi, Sang Ah</creatorcontrib><creatorcontrib>Lee, Dong Hoon</creatorcontrib><creatorcontrib>Kim, Go Woon</creatorcontrib><creatorcontrib>Ryu, Hyun-Wook</creatorcontrib><creatorcontrib>Park, Jong Woo</creatorcontrib><creatorcontrib>Lee, Jaecheol</creatorcontrib><creatorcontrib>Han, Jihoon</creatorcontrib><creatorcontrib>Park, Jee Hun</creatorcontrib><creatorcontrib>Oh, Hwamok</creatorcontrib><creatorcontrib>Lee, Jieun</creatorcontrib><creatorcontrib>Choi, Junjeong</creatorcontrib><creatorcontrib>Kim, Hyun-Soo</creatorcontrib><creatorcontrib>Kang, Hyeok Gu</creatorcontrib><creatorcontrib>Kim, Da-Hyun</creatorcontrib><creatorcontrib>Chun, Kyung-Hee</creatorcontrib><creatorcontrib>You, Jueng Soo</creatorcontrib><creatorcontrib>Han, Jeung-Whan</creatorcontrib><creatorcontrib>Kwon, So Hee</creatorcontrib><title>HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of
UBE2L3
which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of
UBE2L3
by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.</description><subject>38/39</subject><subject>38/89</subject><subject>631/337/176</subject><subject>64/60</subject><subject>692/699/67/1244</subject><subject>82/51</subject><subject>82/80</subject><subject>Active Transport, Cell Nucleus</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - pathology</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell Line, Tumor</subject><subject>Cell Nucleus - metabolism</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Chromosomal Proteins, Non-Histone - metabolism</subject><subject>Cytoplasm</subject><subject>Degradation</subject><subject>Down-Regulation - genetics</subject><subject>Doxycycline - pharmacology</subject><subject>E6 protein</subject><subject>Exportin 1 Protein</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Heterochromatin</subject><subject>Human papillomavirus</subject><subject>Karyopherins - metabolism</subject><subject>Life Sciences</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Models, Biological</subject><subject>Nuclear transport</subject><subject>Oncogene Proteins, Viral - metabolism</subject><subject>p53 Protein</subject><subject>Proteasomes</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein transport</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Repressor Proteins - metabolism</subject><subject>Risk Factors</subject><subject>Stem Cells</subject><subject>Transcription</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumorigenesis</subject><subject>Ubiquitin-Conjugating Enzymes - genetics</subject><subject>Ubiquitin-Conjugating Enzymes - metabolism</subject><subject>Ubiquitination</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - pathology</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kctuFDEQRS0EIiHwAWyQJTZsmvht9wYJRYRBipQsAhsWlseuHhz12IPdPZDvyn_wTXg0ITyksPBDrlPXt3QRek7Ja0q4Oa6CCmo6wkhHZNvkA3RIhVadFIQ_bHcuSdcToQ_Qk1qvCCFK9-oxOuCMEU41O0SfFxefujWE6CYIOM1-BFcwfN_kMuE84MUF_XGDQ4lbqNhD2UbvRjzN61ziChLUWPHyGof8LRVYzaObYk67xo3kT9GjwY0Vnt2eR-jj6bvLk0V3dv7-w8nbs86L3kwd613zrDwxTDni1RDaUobDUkrGQ3tTQF0AxpWW3gXtDQ-CDiAJSOcdP0Jv9rqbedlG8ZCm4ka7KXHtyrXNLtq_Kyl-sau8tVqw3mjZBF7dCpT8dYY62XWsHsbRJchztYw3a4ILYxr68h_0Ks8ltfEsE1qSxvTy_xQXgihqeKPonvIl11pguLNMid0FbPcB2xaw3QVsd8ov_pz1ruNXog1ge6C2UlpB-f31_ao_AYXdsVw</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Yi, Sang Ah</creator><creator>Lee, Dong Hoon</creator><creator>Kim, Go Woon</creator><creator>Ryu, Hyun-Wook</creator><creator>Park, Jong Woo</creator><creator>Lee, Jaecheol</creator><creator>Han, Jihoon</creator><creator>Park, Jee Hun</creator><creator>Oh, Hwamok</creator><creator>Lee, Jieun</creator><creator>Choi, Junjeong</creator><creator>Kim, Hyun-Soo</creator><creator>Kang, Hyeok Gu</creator><creator>Kim, Da-Hyun</creator><creator>Chun, Kyung-Hee</creator><creator>You, Jueng Soo</creator><creator>Han, Jeung-Whan</creator><creator>Kwon, So Hee</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3187-6844</orcidid></search><sort><creationdate>20200901</creationdate><title>HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53</title><author>Yi, Sang Ah ; Lee, Dong Hoon ; Kim, Go Woon ; Ryu, Hyun-Wook ; Park, Jong Woo ; Lee, Jaecheol ; Han, Jihoon ; Park, Jee Hun ; Oh, Hwamok ; Lee, Jieun ; Choi, Junjeong ; Kim, Hyun-Soo ; Kang, Hyeok Gu ; Kim, Da-Hyun ; Chun, Kyung-Hee ; You, Jueng Soo ; Han, Jeung-Whan ; Kwon, So Hee</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-29a4766c0826a0c6fdc6f683eb5523d6a06e1ade23675cad7c83d41fe50e5aca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>38/39</topic><topic>38/89</topic><topic>631/337/176</topic><topic>64/60</topic><topic>692/699/67/1244</topic><topic>82/51</topic><topic>82/80</topic><topic>Active Transport, Cell Nucleus</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - pathology</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell Line, Tumor</topic><topic>Cell Nucleus - metabolism</topic><topic>Cervical cancer</topic><topic>Cervix</topic><topic>Chromosomal Proteins, Non-Histone - metabolism</topic><topic>Cytoplasm</topic><topic>Degradation</topic><topic>Down-Regulation - genetics</topic><topic>Doxycycline - pharmacology</topic><topic>E6 protein</topic><topic>Exportin 1 Protein</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Heterochromatin</topic><topic>Human papillomavirus</topic><topic>Karyopherins - metabolism</topic><topic>Life Sciences</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Models, Biological</topic><topic>Nuclear transport</topic><topic>Oncogene Proteins, Viral - metabolism</topic><topic>p53 Protein</topic><topic>Proteasomes</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein transport</topic><topic>Proteins</topic><topic>Proteolysis</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Repressor Proteins - metabolism</topic><topic>Risk Factors</topic><topic>Stem Cells</topic><topic>Transcription</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumorigenesis</topic><topic>Ubiquitin-Conjugating Enzymes - genetics</topic><topic>Ubiquitin-Conjugating Enzymes - metabolism</topic><topic>Ubiquitination</topic><topic>Uterine Cervical Neoplasms - genetics</topic><topic>Uterine Cervical Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yi, Sang Ah</creatorcontrib><creatorcontrib>Lee, Dong Hoon</creatorcontrib><creatorcontrib>Kim, Go Woon</creatorcontrib><creatorcontrib>Ryu, Hyun-Wook</creatorcontrib><creatorcontrib>Park, Jong Woo</creatorcontrib><creatorcontrib>Lee, Jaecheol</creatorcontrib><creatorcontrib>Han, Jihoon</creatorcontrib><creatorcontrib>Park, Jee Hun</creatorcontrib><creatorcontrib>Oh, Hwamok</creatorcontrib><creatorcontrib>Lee, Jieun</creatorcontrib><creatorcontrib>Choi, Junjeong</creatorcontrib><creatorcontrib>Kim, Hyun-Soo</creatorcontrib><creatorcontrib>Kang, Hyeok Gu</creatorcontrib><creatorcontrib>Kim, Da-Hyun</creatorcontrib><creatorcontrib>Chun, Kyung-Hee</creatorcontrib><creatorcontrib>You, Jueng Soo</creatorcontrib><creatorcontrib>Han, Jeung-Whan</creatorcontrib><creatorcontrib>Kwon, So Hee</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yi, Sang Ah</au><au>Lee, Dong Hoon</au><au>Kim, Go Woon</au><au>Ryu, Hyun-Wook</au><au>Park, Jong Woo</au><au>Lee, Jaecheol</au><au>Han, Jihoon</au><au>Park, Jee Hun</au><au>Oh, Hwamok</au><au>Lee, Jieun</au><au>Choi, Junjeong</au><au>Kim, Hyun-Soo</au><au>Kang, Hyeok Gu</au><au>Kim, Da-Hyun</au><au>Chun, Kyung-Hee</au><au>You, Jueng Soo</au><au>Han, Jeung-Whan</au><au>Kwon, So Hee</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>27</volume><issue>9</issue><spage>2537</spage><epage>2551</epage><pages>2537-2551</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of
UBE2L3
which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of
UBE2L3
by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32203172</pmid><doi>10.1038/s41418-020-0520-5</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-3187-6844</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1350-9047 |
| ispartof | Cell death and differentiation, 2020-09, Vol.27 (9), p.2537-2551 |
| issn | 1350-9047 1476-5403 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7429875 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | 38/39 38/89 631/337/176 64/60 692/699/67/1244 82/51 82/80 Active Transport, Cell Nucleus Animals Apoptosis Biochemistry Biomedical and Life Sciences Carcinogenesis - genetics Carcinogenesis - pathology Cell Biology Cell Cycle Analysis Cell Line, Tumor Cell Nucleus - metabolism Cervical cancer Cervix Chromosomal Proteins, Non-Histone - metabolism Cytoplasm Degradation Down-Regulation - genetics Doxycycline - pharmacology E6 protein Exportin 1 Protein Female Gene Expression Regulation, Neoplastic Heterochromatin Human papillomavirus Karyopherins - metabolism Life Sciences Mice, Inbred BALB C Mice, Nude Models, Biological Nuclear transport Oncogene Proteins, Viral - metabolism p53 Protein Proteasomes Protein Isoforms - metabolism Protein transport Proteins Proteolysis Receptors, Cytoplasmic and Nuclear - metabolism Repressor Proteins - metabolism Risk Factors Stem Cells Transcription Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumorigenesis Ubiquitin-Conjugating Enzymes - genetics Ubiquitin-Conjugating Enzymes - metabolism Ubiquitination Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - pathology |
| title | HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T03%3A21%3A01IST&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=HPV-mediated%20nuclear%20export%20of%20HP1%CE%B3%20drives%20cervical%20tumorigenesis%20by%20downregulation%20of%20p53&rft.jtitle=Cell%20death%20and%20differentiation&rft.au=Yi,%20Sang%20Ah&rft.date=2020-09-01&rft.volume=27&rft.issue=9&rft.spage=2537&rft.epage=2551&rft.pages=2537-2551&rft.issn=1350-9047&rft.eissn=1476-5403&rft_id=info:doi/10.1038/s41418-020-0520-5&rft_dat=%3Cproquest_pubme%3E2382643488%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2434406183&rft_id=info:pmid/32203172&rfr_iscdi=true |