Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death.
Identifieur interne : 000212 ( PubMed/Curation ); précédent : 000211; suivant : 000213Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death.
Auteurs : Ke Jiang [République populaire de Chine] ; Min Liu [République populaire de Chine] ; Guibin Lin [République populaire de Chine] ; Beibei Mao [République populaire de Chine] ; Wei Cheng [République populaire de Chine] ; Han Liu [République populaire de Chine] ; Jozsef Gal [États-Unis] ; Haining Zhu [États-Unis] ; Zengqiang Yuan [République populaire de Chine] ; Wuguo Deng [République populaire de Chine] ; Quentin Liu [République populaire de Chine] ; Peng Gong [République populaire de Chine] ; Xiaolin Bi [République populaire de Chine] ; Songshu Meng [République populaire de Chine]Source :
- Oncotarget [ 1949-2553 ] ; 2016.
Descripteurs français
- KwdFr :
- MESH :
- métabolisme : Autophagosomes, Protéines associées aux microtubules, Protéines de répression.
- physiologie : Autophagie.
- Humains, Lignée cellulaire tumorale.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Microtubule-Associated Proteins, Repressor Proteins.
- metabolism : Autophagosomes.
- physiology : Autophagy.
- Cell Line, Tumor, Humans.
Abstract
The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner.
DOI: 10.18632/oncotarget.8357
PubMed: 27028858
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populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Quentin" sort="Liu, Quentin" uniqKey="Liu Q" first="Quentin" last="Liu">Quentin Liu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Gong, Peng" sort="Gong, Peng" uniqKey="Gong P" first="Peng" last="Gong">Peng Gong</name><affiliation wicri:level="1"><nlm:affiliation>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de 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wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Min" sort="Liu, Min" uniqKey="Liu M" first="Min" last="Liu">Min Liu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Lin, Guibin" sort="Lin, Guibin" uniqKey="Lin G" first="Guibin" last="Lin">Guibin Lin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Mao, Beibei" sort="Mao, Beibei" uniqKey="Mao B" first="Beibei" last="Mao">Beibei Mao</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Cheng, Wei" sort="Cheng, Wei" uniqKey="Cheng W" first="Wei" last="Cheng">Wei Cheng</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Han" sort="Liu, Han" uniqKey="Liu H" first="Han" last="Liu">Han Liu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Gal, Jozsef" sort="Gal, Jozsef" uniqKey="Gal J" first="Jozsef" last="Gal">Jozsef Gal</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky</wicri:regionArea></affiliation></author><author><name sortKey="Zhu, Haining" sort="Zhu, Haining" uniqKey="Zhu H" first="Haining" last="Zhu">Haining Zhu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky</wicri:regionArea></affiliation></author><author><name sortKey="Yuan, Zengqiang" sort="Yuan, Zengqiang" uniqKey="Yuan Z" first="Zengqiang" last="Yuan">Zengqiang Yuan</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Deng, Wuguo" sort="Deng, Wuguo" uniqKey="Deng W" first="Wuguo" last="Deng">Wuguo Deng</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Quentin" sort="Liu, Quentin" uniqKey="Liu Q" first="Quentin" last="Liu">Quentin Liu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Gong, Peng" sort="Gong, Peng" uniqKey="Gong P" first="Peng" last="Gong">Peng Gong</name><affiliation wicri:level="1"><nlm:affiliation>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Bi, Xiaolin" sort="Bi, Xiaolin" uniqKey="Bi X" first="Xiaolin" last="Bi">Xiaolin Bi</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author><author><name sortKey="Meng, Songshu" sort="Meng, Songshu" uniqKey="Meng S" first="Songshu" last="Meng">Songshu Meng</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian</wicri:regionArea></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autophagosomes (metabolism)</term><term>Autophagy (physiology)</term><term>Cell Line, Tumor</term><term>Humans</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Repressor Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Autophagie (physiologie)</term><term>Autophagosomes (métabolisme)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Protéines associées aux microtubules (métabolisme)</term><term>Protéines de répression (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Microtubule-Associated Proteins</term><term>Repressor Proteins</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Autophagosomes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Autophagosomes</term><term>Protéines associées aux microtubules</term><term>Protéines de répression</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Autophagie</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Autophagy</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Lignée cellulaire tumorale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27028858</PMID><DateCompleted><Year>2018</Year><Month>01</Month><Day>05</Day></DateCompleted><DateRevised><Year>2019</Year><Month>02</Month><Day>16</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>7</Volume><Issue>18</Issue><PubDate><Year>2016</Year><Month>May</Month><Day>03</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death.</ArticleTitle><Pagination><MedlinePgn>25652-67</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.8357</ELocationID><Abstract><AbstractText>The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Jiang</LastName><ForeName>Ke</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Min</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lin</LastName><ForeName>Guibin</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mao</LastName><ForeName>Beibei</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cheng</LastName><ForeName>Wei</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Han</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gal</LastName><ForeName>Jozsef</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhu</LastName><ForeName>Haining</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yuan</LastName><ForeName>Zengqiang</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Deng</LastName><ForeName>Wuguo</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Quentin</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gong</LastName><ForeName>Peng</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bi</LastName><ForeName>Xiaolin</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Meng</LastName><ForeName>Songshu</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 CA177558</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Oncotarget</MedlineTA><NlmUniqueID>101532965</NlmUniqueID><ISSNLinking>1949-2553</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008869">Microtubule-Associated Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D012097">Repressor Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C500760">SPRED2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C466626">light chain 3, human</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000071182" MajorTopicYN="N">Autophagosomes</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008869" MajorTopicYN="N">Microtubule-Associated Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012097" MajorTopicYN="N">Repressor Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">LC3</Keyword><Keyword MajorTopicYN="N">Spred2</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">p62/SQSTM1</Keyword><Keyword MajorTopicYN="N">tumor suppressor</Keyword></KeywordList><CoiStatement>The authors have declared that no competing financial interests exist.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>04</Month><Day>13</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>03</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>3</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>3</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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