Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence

Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed oncogene-induced senescence or OIS). We and others have previously demonstrated that OIS occurs in human benign lesions, acting as a potent t...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Carcinogenesis (New York) Jg. 36; H. 11; S. 1263
Hauptverfasser:	Lenain, Christelle, Gusyatiner, Olga, Douma, Sirith, van den Broek, Bram, Peeper, Daniel S
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England 01.11.2015
Schlagworte:	Autophagy Cell Line Cell Nucleus Shape Cellular Senescence Humans Nuclear Envelope - metabolism Nuclear Proteins - metabolism Oncogenes Proteolysis
ISSN:	1460-2180, 1460-2180
Online-Zugang:	Weitere Angaben
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Abstract	Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed oncogene-induced senescence or OIS). We and others have previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism. Numerous phenotypic changes occur during OIS, both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAF(V600E)- or H-RAS(G12V)-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins, resulting in an altered NE morphology. Depletion of LMNB1 or LMNA/C was sufficient to recapitulate some OIS features, including cell cycle exit and downregulation of NE proteins. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery, which occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study therefore reveals a previously unknown connection between autophagy and the disruption of NE integrity during OIS.
AbstractList	Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed oncogene-induced senescence or OIS). We and others have previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism. Numerous phenotypic changes occur during OIS, both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAF(V600E)- or H-RAS(G12V)-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins, resulting in an altered NE morphology. Depletion of LMNB1 or LMNA/C was sufficient to recapitulate some OIS features, including cell cycle exit and downregulation of NE proteins. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery, which occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study therefore reveals a previously unknown connection between autophagy and the disruption of NE integrity during OIS.Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed oncogene-induced senescence or OIS). We and others have previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism. Numerous phenotypic changes occur during OIS, both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAF(V600E)- or H-RAS(G12V)-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins, resulting in an altered NE morphology. Depletion of LMNB1 or LMNA/C was sufficient to recapitulate some OIS features, including cell cycle exit and downregulation of NE proteins. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery, which occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study therefore reveals a previously unknown connection between autophagy and the disruption of NE integrity during OIS. Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed oncogene-induced senescence or OIS). We and others have previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism. Numerous phenotypic changes occur during OIS, both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAF(V600E)- or H-RAS(G12V)-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins, resulting in an altered NE morphology. Depletion of LMNB1 or LMNA/C was sufficient to recapitulate some OIS features, including cell cycle exit and downregulation of NE proteins. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery, which occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study therefore reveals a previously unknown connection between autophagy and the disruption of NE integrity during OIS.
Author	Gusyatiner, Olga Lenain, Christelle Douma, Sirith van den Broek, Bram Peeper, Daniel S
Author_xml	– sequence: 1 givenname: Christelle surname: Lenain fullname: Lenain, Christelle organization: Division of Molecular Oncology and – sequence: 2 givenname: Olga surname: Gusyatiner fullname: Gusyatiner, Olga organization: Division of Molecular Oncology and Present address: Laboratory of Brain Tumor Biology and Genetics, Department of Neurosurgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland – sequence: 3 givenname: Sirith surname: Douma fullname: Douma, Sirith organization: Division of Molecular Oncology and – sequence: 4 givenname: Bram surname: van den Broek fullname: van den Broek, Bram organization: Division of Cell Biology I, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 5 givenname: Daniel S surname: Peeper fullname: Peeper, Daniel S email: d.peeper@nki.nl organization: Division of Molecular Oncology and d.peeper@nki.nl
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/26354777$$D View this record in MEDLINE/PubMed
BookMark	eNpNUE1LxDAUDKK4H3r0Kj16qZuvbZPjsvgFC170asnHa410k5q0C_vvDbiClzfvDcMw8xbo3AcPCN0QfE-wZCujonF-pbsDofwMzQmvcEmJwOf_9hlapPSFManYWl6iGc3I67qeo4_NNIbhU3XHcg_WqRFsYaGLyqrRBV-EtvCT6UHFAvwB-jBAMcQwgvOpsFN0viuCN6EDD6XzdjLZIOUjGfAGrtBFq_oE1ydcovfHh7ftc7l7fXrZbnalYVKMpSTY1pwpobTWeRigpK2krizhmZdSS9xaTTGuGKYt5pRh4EIJWlGhuaZLdPfrm7N9T5DGZu9ygr5XHsKUGlJTUdWM8XWW3p6kk86VmyG6vYrH5u8n9Ae9_Wdg
CitedBy_id	crossref_primary_10_1038_s43587_022_00186_z crossref_primary_10_1042_BCJ20200165 crossref_primary_10_1080_15384101_2016_1234547 crossref_primary_10_1038_s41388_019_0798_2 crossref_primary_10_1016_j_mad_2019_111118 crossref_primary_10_3390_cells6030028 crossref_primary_10_1016_j_yexcr_2019_03_002 crossref_primary_10_1042_BCJ20160459 crossref_primary_10_1038_s41467_021_26224_9 crossref_primary_10_1016_j_cub_2017_09_043 crossref_primary_10_1083_jcb_202205123 crossref_primary_10_1016_j_tcb_2019_12_008 crossref_primary_10_1186_s13046_019_1048_8 crossref_primary_10_1016_j_arr_2021_101458 crossref_primary_10_1002_cbin_11504 crossref_primary_10_1007_s00335_016_9628_9 crossref_primary_10_1016_j_ceb_2016_03_004 crossref_primary_10_3389_fonc_2019_00022 crossref_primary_10_1002_ptr_6636 crossref_primary_10_1124_pharmrev_122_000622 crossref_primary_10_1007_s00418_018_1726_1 crossref_primary_10_1007_s42764_021_00039_w crossref_primary_10_1002_jcp_31213 crossref_primary_10_1038_s44318_024_00192_4 crossref_primary_10_3390_cells9061340 crossref_primary_10_3390_cells14040282 crossref_primary_10_3390_ijms242115771 crossref_primary_10_1016_j_cub_2018_01_073 crossref_primary_10_1111_apha_13374 crossref_primary_10_1038_s41467_024_54338_3 crossref_primary_10_1080_15548627_2016_1217381 crossref_primary_10_1016_j_mad_2019_01_001 crossref_primary_10_1002_1878_0261_13269 crossref_primary_10_1101_gad_320937_118 crossref_primary_10_1016_j_bcp_2022_114989 crossref_primary_10_1016_j_tig_2016_09_005 crossref_primary_10_1007_s00412_020_00741_w crossref_primary_10_1016_j_ceb_2023_102220 crossref_primary_10_1038_nrm_2016_153 crossref_primary_10_1016_j_yexcr_2020_111927 crossref_primary_10_3390_cells8020136 crossref_primary_10_3390_cells12162045 crossref_primary_10_1038_s41401_023_01112_8 crossref_primary_10_1172_JCI178920 crossref_primary_10_1242_jcs_260563 crossref_primary_10_1016_j_mrrev_2018_11_001 crossref_primary_10_1093_neuonc_noab115 crossref_primary_10_1101_gr_225763_117 crossref_primary_10_1111_boc_202000160
ContentType	Journal Article
Copyright	The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Copyright_xml	– notice: The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
DBID	CGR CUY CVF ECM EIF NPM 7X8
DOI	10.1093/carcin/bgv124
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic
DatabaseTitleList	MEDLINE - Academic MEDLINE
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database
DeliveryMethod	no_fulltext_linktorsrc
Discipline	Medicine
EISSN	1460-2180
ExternalDocumentID	26354777
Genre	Research Support, Non-U.S. Gov't Journal Article
GroupedDBID	--- -E4 .2P .55 .GJ .I3 .ZR 0R~ 18M 1TH 29B 2WC 3O- 4.4 482 48X 53G 5GY 5RE 5VS 5WA 5WD 6J9 70D A8Z AABZA AACZT AAIMJ AAJKP AAJQQ AAMDB AAMVS AAOGV AAPGJ AAPNW AAPQZ AAPXW AARHZ AAUAY AAUQX AAVAP AAVLN AAWDT ABDFA ABEFU ABEJV ABEUO ABGNP ABIME ABIXL ABJNI ABKDP ABLJU ABMNT ABNHQ ABNKS ABPIB ABPQP ABPTD ABQLI ABSMQ ABVGC ABWST ABXVV ABXZS ABZBJ ABZEO ACFRR ACGFO ACGFS ACNCT ACPQN ACPRK ACUFI ACUTJ ACUTO ACVCV ACZBC ADBBV ADEYI ADEZT ADFTL ADGKP ADGZP ADHKW ADHZD ADIPN ADMTO ADNBA ADOCK ADQBN ADRTK ADVEK ADYVW ADZTZ ADZXQ AEGPL AEGXH AEHUL AEJOX AEKPW AEKSI AELWJ AEMDU AENEX AENZO AEPUE AETBJ AEWNT AFFNX AFFQV AFFZL AFGWE AFIYH AFOFC AFRAH AFSHK AFYAG AGINJ AGKEF AGKRT AGMDO AGORE AGQPQ AGQXC AGSYK AHGBF AHMBA AHMMS AHXPO AIAGR AIJHB AJBYB AJDVS AJEEA AJNCP AKHUL AKWXX ALMA_UNASSIGNED_HOLDINGS ALUQC ALXQX ANFBD APIBT APJGH APWMN AQDSO AQKUS ARIXL ASAOO ASPBG ATDFG ATGXG ATTQO AVNTJ AVWKF AXUDD AYOIW AZFZN BAWUL BAYMD BCRHZ BEYMZ BHONS BQDIO BSWAC BTRTY BVRKM BZKNY C1A C45 CAG CDBKE CGR COF CS3 CUY CVF CXTWN CZ4 DAKXR DFGAJ DIK DILTD DU5 D~K E3Z EBD EBS ECM EE~ EIF EIHJH EJD ELUNK EMOBN F5P F9B FEDTE FHSFR FLUFQ FOEOM FOTVD FQBLK GAUVT GJXCC GX1 H13 H5~ HAR HVGLF HW0 HZ~ IH2 IOX J21 JXSIZ KAQDR KBUDW KOP KQ8 KSI KSN M-Z MBLQV MBTAY N9A NGC NLBLG NOMLY NOYVH NPM NTWIH NU- NVLIB O0~ O9- OAWHX OBFPC OBOKY OCZFY ODMLO OJQWA OJZSN OK1 OPAEJ OVD OWPYF O~Y P2P PAFKI PB- PEELM PQQKQ Q1. Q5Y QBD R44 RD5 RIG RNI ROL ROX ROZ RUSNO RW1 RXO RZF RZO SV3 TCN TEORI TJX TLC TMA TR2 W8F WOQ X7H X7M XOL YAYTL YKOAZ YXANX ZGI ZKB ZKX ZXP ~91 7X8 ESTFP
ID	FETCH-LOGICAL-c398t-910d743a8abbb8abce21f69b6d1474399b90fdb2006302f04230e48a82628b4b2
IEDL.DBID	7X8
ISICitedReferencesCount	53
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000366386800002&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	1460-2180
IngestDate	Thu Oct 02 15:51:18 EDT 2025 Mon Jul 21 05:51:18 EDT 2025
IsDoiOpenAccess	false
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Issue	11
Language	English
License	The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c398t-910d743a8abbb8abce21f69b6d1474399b90fdb2006302f04230e48a82628b4b2
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
OpenAccessLink	https://academic.oup.com/carcin/article-pdf/36/11/1263/1055076/bgv124.pdf
PMID	26354777
PQID	1728673345
PQPubID	23479
ParticipantIDs	proquest_miscellaneous_1728673345 pubmed_primary_26354777
PublicationCentury	2000
PublicationDate	2015-11-01
PublicationDateYYYYMMDD	2015-11-01
PublicationDate_xml	– month: 11 year: 2015 text: 2015-11-01 day: 01
PublicationDecade	2010
PublicationPlace	England
PublicationPlace_xml	– name: England
PublicationTitle	Carcinogenesis (New York)
PublicationTitleAlternate	Carcinogenesis
PublicationYear	2015
SSID	ssj0016359
Score	2.4088914
Snippet	Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types of damage and stress, including oncogene expression (termed...
SourceID	proquest pubmed
SourceType	Aggregation Database Index Database
StartPage	1263
SubjectTerms	Autophagy Cell Line Cell Nucleus Shape Cellular Senescence Humans Nuclear Envelope - metabolism Nuclear Proteins - metabolism Oncogenes Proteolysis
Title	Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence
URI	https://www.ncbi.nlm.nih.gov/pubmed/26354777 https://www.proquest.com/docview/1728673345
Volume	36
WOSCitedRecordID	wos000366386800002&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText
inHoldings	1
isFullTextHit
isPrint
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LSwMxEA5qRbz4fj-I4DV0H9nN7kmKKF5aelDoySXP0ku2dm3Bf-9MdosnQfCSQ2AhDLMz32Qy30fIvcEkJoVlUmWacZM6pix3rMhVnsvC8Sw2QWxCjEbFZFKOuwu3pntWuY6JIVCbWuMdeR91lHKRpjx7mH8wVI3C7monobFJeilAGfRqMfnpIsA5yna6KGKQyqKOYxOK-L5GpR7fV9NVjMPuv6HLkGWe9_97vgOy1-FLOmgd4pBsWH9EdoZdB_2YvA-WSCUgp18sDI0A4KQGCSNabSVaO-qR4lguqPXhPZGlgcth5hvazjTS2usa_M4yqOfBMwxtMGBqjBEn5O356fXxhXUaC0ynZfEJsS4yACJkIZVSsGibxC4vVW5iHmoVVUbOqCRwcyUOX9FElhcSqpKkUFwlp2TL196eE5pksMmTSArHObeJEpnOrRA6NgJp5y_I3dpyFfgwNiakt_WyqX5sd0HOWvNX85Zso0KyHC6EuPzD11dkF_BM1o4KXpOegz_Y3pBtvfqcNYvb4BywjsbDbyl_xmA
linkProvider	ProQuest
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Autophagy-mediated+degradation+of+nuclear+envelope+proteins+during+oncogene-induced+senescence&rft.jtitle=Carcinogenesis+%28New+York%29&rft.au=Lenain%2C+Christelle&rft.au=Gusyatiner%2C+Olga&rft.au=Douma%2C+Sirith&rft.au=van+den+Broek%2C+Bram&rft.date=2015-11-01&rft.eissn=1460-2180&rft.volume=36&rft.issue=11&rft.spage=1263&rft_id=info:doi/10.1093%2Fcarcin%2Fbgv124&rft_id=info%3Apmid%2F26354777&rft_id=info%3Apmid%2F26354777&rft.externalDocID=26354777
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1460-2180&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1460-2180&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1460-2180&client=summon