The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB–Inducing Kinase
Identifieur interne : 000D64 ( Ncbi/Merge ); précédent : 000D63; suivant : 000D65The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB–Inducing Kinase
Auteurs : Hanbit Jang [Corée du Sud] ; Seulki Park [Corée du Sud] ; Jaehoon Kim [Corée du Sud] ; Jong Hwan Kim [Corée du Sud] ; Seon-Young Kim [Corée du Sud] ; Sayeon Cho [Corée du Sud] ; Sung Goo Park [Corée du Sud] ; Byoung Chul Park [Corée du Sud] ; Sunhong Kim [Corée du Sud] ; Jeong-Hoon Kim [Corée du Sud]Source :
- Molecules and Cells [ 1016-8478 ] ; 2019.
Abstract
NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB–inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the
Url:
DOI: 10.14348/molcells.2019.0239
PubMed: 31870133
PubMed Central: 6999715
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB–Inducing Kinase</title><author><name sortKey="Jang, Hanbit" sort="Jang, Hanbit" uniqKey="Jang H" first="Hanbit" last="Jang">Hanbit Jang</name><affiliation wicri:level="1"><nlm:aff id="af1-molce-43-023">Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Seulki" sort="Park, Seulki" uniqKey="Park S" first="Seulki" last="Park">Seulki Park</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molce-43-023">Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jaehoon" sort="Kim, Jaehoon" uniqKey="Kim J" first="Jaehoon" last="Kim">Jaehoon Kim</name><affiliation wicri:level="1"><nlm:aff id="af1-molce-43-023">Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jong Hwan" sort="Kim, Jong Hwan" uniqKey="Kim J" first="Jong Hwan" last="Kim">Jong Hwan Kim</name><affiliation wicri:level="1"><nlm:aff id="af6-molce-43-023">Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Seon Young" sort="Kim, Seon Young" uniqKey="Kim S" first="Seon-Young" last="Kim">Seon-Young Kim</name><affiliation wicri:level="1"><nlm:aff id="af6-molce-43-023">Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cho, Sayeon" sort="Cho, Sayeon" uniqKey="Cho S" first="Sayeon" last="Cho">Sayeon Cho</name><affiliation wicri:level="1"><nlm:aff id="af7-molce-43-023">College of Pharmacy, Chung-Ang University, Seoul 06974,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Sung Goo" sort="Park, Sung Goo" uniqKey="Park S" first="Sung Goo" last="Park">Sung Goo Park</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molce-43-023">Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Byoung Chul" sort="Park, Byoung Chul" uniqKey="Park B" first="Byoung Chul" last="Park">Byoung Chul Park</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-molce-43-023">Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Sunhong" sort="Kim, Sunhong" uniqKey="Kim S" first="Sunhong" last="Kim">Sunhong Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-molce-43-023">Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jeong Hoon" sort="Kim, Jeong Hoon" uniqKey="Kim J" first="Jeong-Hoon" last="Kim">Jeong-Hoon Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molce-43-023">Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31870133</idno><idno type="pmc">6999715</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999715</idno><idno type="RBID">PMC:6999715</idno><idno type="doi">10.14348/molcells.2019.0239</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000703</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000703</idno><idno type="wicri:Area/Pmc/Curation">000703</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000703</idno><idno type="wicri:Area/Pmc/Checkpoint">000316</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000316</idno><idno type="wicri:Area/Ncbi/Merge">000D64</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNA-Induced Silencing of NF-κB–Inducing Kinase</title><author><name sortKey="Jang, Hanbit" sort="Jang, Hanbit" uniqKey="Jang H" first="Hanbit" last="Jang">Hanbit Jang</name><affiliation wicri:level="1"><nlm:aff id="af1-molce-43-023">Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Seulki" sort="Park, Seulki" uniqKey="Park S" first="Seulki" last="Park">Seulki Park</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molce-43-023">Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jaehoon" sort="Kim, Jaehoon" uniqKey="Kim J" first="Jaehoon" last="Kim">Jaehoon Kim</name><affiliation wicri:level="1"><nlm:aff id="af1-molce-43-023">Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jong Hwan" sort="Kim, Jong Hwan" uniqKey="Kim J" first="Jong Hwan" last="Kim">Jong Hwan Kim</name><affiliation wicri:level="1"><nlm:aff id="af6-molce-43-023">Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Seon Young" sort="Kim, Seon Young" uniqKey="Kim S" first="Seon-Young" last="Kim">Seon-Young Kim</name><affiliation wicri:level="1"><nlm:aff id="af6-molce-43-023">Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cho, Sayeon" sort="Cho, Sayeon" uniqKey="Cho S" first="Sayeon" last="Cho">Sayeon Cho</name><affiliation wicri:level="1"><nlm:aff id="af7-molce-43-023">College of Pharmacy, Chung-Ang University, Seoul 06974,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Sung Goo" sort="Park, Sung Goo" uniqKey="Park S" first="Sung Goo" last="Park">Sung Goo Park</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molce-43-023">Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Byoung Chul" sort="Park, Byoung Chul" uniqKey="Park B" first="Byoung Chul" last="Park">Byoung Chul Park</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-molce-43-023">Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Sunhong" sort="Kim, Sunhong" uniqKey="Kim S" first="Sunhong" last="Kim">Sunhong Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-molce-43-023">Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jeong Hoon" sort="Kim, Jeong Hoon" uniqKey="Kim J" first="Jeong-Hoon" last="Kim">Jeong-Hoon Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-molce-43-023">Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molce-43-023">Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecules and Cells</title><idno type="ISSN">1016-8478</idno><idno type="eISSN">0219-1032</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB–inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the <italic>TP53</italic> gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Balaji, S" uniqKey="Balaji S">S. Balaji</name></author><author><name sortKey="Ahmed, M" uniqKey="Ahmed M">M. Ahmed</name></author><author><name sortKey="Lorence, E" uniqKey="Lorence E">E. Lorence</name></author><author><name sortKey="Yan, F" uniqKey="Yan F">F. Yan</name></author><author><name sortKey="Nomie, K" uniqKey="Nomie K">K. Nomie</name></author><author><name sortKey="Wang, M" uniqKey="Wang M">M. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bartel, D P" uniqKey="Bartel D">D.P. Bartel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beg, M S" uniqKey="Beg M">M.S. 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contrib-type="author"><name><surname>Jang</surname><given-names>Hanbit</given-names></name><xref ref-type="aff" rid="af1-molce-43-023">1</xref><xref ref-type="aff" rid="af2-molce-43-023">2</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-1139-5506</contrib-id></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Seulki</given-names></name><xref ref-type="aff" rid="af2-molce-43-023">2</xref><xref ref-type="aff" rid="af3-molce-43-023">3</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-7441-8010</contrib-id></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jaehoon</given-names></name><xref ref-type="aff" rid="af1-molce-43-023">1</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4035-0438</contrib-id></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jong Hwan</given-names></name><xref ref-type="aff" rid="af6-molce-43-023">6</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-9520-0771</contrib-id></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Seon-Young</given-names></name><xref ref-type="aff" rid="af6-molce-43-023">6</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-1030-7730</contrib-id></contrib><contrib contrib-type="author"><name><surname>Cho</surname><given-names>Sayeon</given-names></name><xref ref-type="aff" rid="af7-molce-43-023">7</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8950-5704</contrib-id></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Sung Goo</given-names></name><xref ref-type="aff" rid="af2-molce-43-023">2</xref><xref ref-type="aff" rid="af3-molce-43-023">3</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-1584-2644</contrib-id></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Byoung Chul</given-names></name><xref ref-type="aff" rid="af2-molce-43-023">2</xref><xref ref-type="aff" rid="af4-molce-43-023">4</xref><xref rid="c1-molce-43-023" ref-type="corresp">*</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8879-5551</contrib-id></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Sunhong</given-names></name><xref ref-type="aff" rid="af2-molce-43-023">2</xref><xref ref-type="aff" rid="af5-molce-43-023">5</xref><xref rid="c1-molce-43-023" ref-type="corresp">*</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-1782-6613</contrib-id></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jeong-Hoon</given-names></name><xref ref-type="aff" rid="af2-molce-43-023">2</xref><xref ref-type="aff" rid="af3-molce-43-023">3</xref><xref rid="c1-molce-43-023" ref-type="corresp">*</xref><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-6338-7175</contrib-id></contrib></contrib-group><aff id="af1-molce-43-023"><label>1</label>Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,<country>Korea</country></aff><aff id="af2-molce-43-023"><label>2</label>Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,<country>Korea</country></aff><aff id="af3-molce-43-023"><label>3</label>Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></aff><aff id="af4-molce-43-023"><label>4</label>Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></aff><aff id="af5-molce-43-023"><label>5</label>Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,<country>Korea</country></aff><aff id="af6-molce-43-023"><label>6</label>Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,<country>Korea</country></aff><aff id="af7-molce-43-023"><label>7</label>College of Pharmacy, Chung-Ang University, Seoul 06974,<country>Korea</country></aff><author-notes><corresp id="c1-molce-43-023"><label>*</label>Correspondence: <email>parkbc@kribb.re.kr</email> (BCP); <email>sunhong@kribb.re.kr</email> (SK); <email>jhoonkim@kribb.re.kr</email> (JHK)</corresp></author-notes><pub-date pub-type="ppub"><month>1</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>24</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>24</day><month>12</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>43</volume><issue>1</issue><fpage>23</fpage><lpage>33</lpage><history><date date-type="received"><day>22</day><month>10</month><year>2019</year></date><date date-type="rev-recd"><day>26</day><month>11</month><year>2019</year></date><date date-type="accepted"><day>27</day><month>11</month><year>2019</year></date></history><permissions><copyright-statement>© The Korean Society for Molecular and Cellular Biology. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><license><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-sa/3.0/">http://creativecommons.org/licenses/by-nc-sa/3.0/</ext-link>.</license-p></license></permissions><abstract><p>NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB–inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the <italic>TP53</italic> gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.</p></abstract><kwd-group><kwd>cancer</kwd><kwd>microRNA</kwd><kwd>NF-κB</kwd><kwd>NF-κB-inducing kinase</kwd><kwd>p53</kwd><kwd>tumor suppressor gene</kwd></kwd-group></article-meta></front><floats-group><fig id="f1-molce-43-023" orientation="portrait" position="float"><label>Fig. 1</label><caption><title>Identification of p53 as a negative regulator of NIK protein and the non-canonical NF-κB pathway via RNAi screening</title><p>(A) Quantification of NIK protein abundance upon tumor suppressor gene knockdown. HeLa cells were electroporated individually with control scrambled siRNA, 50 nM siRNAs targeting 15 tumor suppressor genes or 50 nM siRNAs targeting BIRC3 for 24 h, followed by transfection with a NIK expression plasmid for 24 h. The relative protein levels of gene-specific knockdown cells were normalized to those of control scrambled siRNA-treated cells. Tumor suppressor genes; APC, adenomatous polyposis coli; ATM, ataxia telangiectasia mutated; BRCA1, breast cancer 1; BRCA2, breast cancer 2; CDH1, E-cadherin; CDKN2C, cyclin-dependent kinase inhibitor 2C; CYLD, cylindromatosis; NF1, neurofibromin 1; NF2, neurofibromin 2; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; SUFU, suppressor of fused homolog; TP53, tumor protein p53; VHL, von Hippel–Lindau tumor suppressor; WT1, Wilms tumor 1. Data represent mean ± SEM. *<italic>P</italic> ≤ 0.05 with Student’s <italic>t</italic>-test. (B) HeLa cells were electroporated with control scrambled siRNA or 50 nM si-TP53 for 24 h, followed by transfection with NIK expression plasmid for 24 h. Lysates of HeLa cells depleted of p53 were analyzed via immunoblotting with antibodies against NIK, p53 or GAPDH as loading control. (C) U2OS cells were electroporated with control scrambled siRNA or 50 nM si-TP53 for 24 h, followed by transfection with control vector or NIK expression plasmid for 48 h. U2OS cell lysates depleted of p53 were analyzed via immunoblotting with antibodies against NIK, p53 or β-actin as a loading control. (D) Z138 cells stably expressing control scrambled shRNA or shRNA specific for p53 were lysed and subjected to immunoblot analysis. (E) HeLa cells stably expressing control scrambled shRNA or shRNA specific for p53 were either left untreated or treated with LIGHT (100 ng/ml) for the indicated time-periods.</p></caption><graphic xlink:href="molce-43-023f1"></graphic></fig><fig id="f2-molce-43-023" orientation="portrait" position="float"><label>Fig. 2</label><caption><title>p53 suppresses protein levels of NIK and non-canonical NF-κB activity</title><p>(A) U2OS cells were transiently transfected with control vector, NIK expression plasmid or various amounts of p53 expression plasmid for 24 h. (B) Z138 cells treated with 10 μM nutlin-3a for indicated time-periods were lysed and subjected to immunoblot analysis. (C) H1299 cells were cotransfected with control vector, a NF-κB–luciferase reporter gene plasmid and expression plasmids for NIK, p53-WT or p53-mTAD as indicated. At 24 h after transfection, H1299 cells were lysed and monitored via the dual-luciferase assay. <italic>Firefly</italic> luciferase activities were normalized to that of Renilla luciferase. Values are presented as an average of duplicates for a representative experiment. Data represent mean ± SEM. *<italic>P</italic> < 0.05 versus the corresponding control; <sup>†</sup><italic>P</italic> < 0.05 for the indicated comparisons; ns, not significant with Student’s <italic>t</italic>-test. (D) H1299 cells were transfected with control vector and expression plasmids for NIK, FLAG-p53-WT, FLAG-p53-mTAD or FLAG-p53-mNLS. Various amounts of the p53 constructs were transfected into H1299 cells. After 48 h, H1299 cell lysates were analyzed via immunoblotting with antibodies against FLAG for detection of p53-WT or p53 mutants.</p></caption><graphic xlink:href="molce-43-023f2"></graphic></fig><fig id="f3-molce-43-023" orientation="portrait" position="float"><label>Fig. 3</label><caption><title>p53 suppresses the expression of NIK through miRNA-mediated gene silencing, but not UPS or lysosomal degradation</title><p>(A) H1299 cells were transfected with control vector and expression plasmids for NIK or p53. After 6 h, cells were incubated in the absence or presence of 2 μM bortezomib (BZM), 100 μM chloroquine (CQ), 0.1 μM bafilomycin A1 (B-A1), 5 mM 3-methyladenine (3-MA) or 10 μM E-64. After 12 h, H1299 cells were lysed and subjected to immunoblot analysis. (B) HeLa cells were electroporated with control scrambled siRNA or 50 nM si-SQSTM1 for 24 h, followed by transfection with control vector or expression plasmids for NIK or various amounts of p53 for 24 h. (C) H1299 cells were transfected with control vector and expression plasmids for NIK or various amounts of p53 for 48 h. Total RNA isolated from H1299 cells was subjected to RT-qPCR analysis for NIK mRNA. Levels of NIK mRNA were normalized to β-actin in the same sample. (D) Total RNA was isolated from Z138 cells stably expressing control scrambled shRNA or shRNA specific for p53 and subjected to RT-qPCR analysis of mRNA for NIK. (E) H1299 cells were electroporated with control scrambled siRNA or siRNAs targeting DROSHA or DICER for 36 h, followed by transfection with control vector or expression plasmids for NIK or various amounts of p53 for 24 h. (F) Densitometric analysis of the immunoblot shown in Figure 3Es. Intensity of NIK bands normalized to that of β-actin. Values are presented as an average of two independent experiments. (G) Upper panels: Full-length CDS of NIK was attached to the 3′ end of <italic>Firefly</italic> luciferase of pCMV-pGL3-Luciferase plasmid (Luc-NIK-CDS) and cotransfected into H1299 cells with control vector and expression plasmids for FLAG-p53-WT, FLAG-p53-mTAD or FLAG-p53-R175H. After 48 h transfection, H1299 cells were lysed, followed by the dual luciferase assay. Activities of the Luc-NIK-CDS reporter were normalized to that of cotransfected CMV-Renilla construct. Lower panels: H1299 cell lysates used for luciferase assays were analyzed via immunoblotting with antibodies against FLAG for detection of p53-WT or p53 mutants. (H) Upper panels: HeLa cells were electroporated with control scrambled siRNA or 50 nM si-TP53 for 24 h, followed by transfection with the Luc-NIK-CDS reporter construct, and subjected to the dual luciferase assay. Activity of the Luc-NIK-CDS reporter was normalized to that of the cotransfected CMV-Renilla construct after 24 h transfection. Lower panels: HeLa cells were analyzed via immunoblotting with antibodies against p53. Quantitative data in Figures 3C, 3D, 3F, 3G, and 3H represent mean ± SEM. *<italic>P</italic> < 0.05; **<italic>P</italic> < 0.005 versus the corresponding control; <sup>†</sup><italic>P</italic> < 0.05; <sup>††</sup><italic>P</italic> < 0.005 for the indicated comparisons with Student’s t-test.</p></caption><graphic xlink:href="molce-43-023f3"></graphic></fig><fig id="f4-molce-43-023" orientation="portrait" position="float"><label>Fig. 4</label><caption><title>p53-induced miR-34b negatively regulates the non-canonical NF-κB pathway by targeting the CDS of NIK</title><p>(A) Heat map for upregulated miRNAs in Z138 treated with 10 μM nutlin-3a for 6 h identified via small RNA sequencing. Total RNA isolated from Z138 cells using the mirVana miRNA isolation kit was used for preparation of small RNA libraries, followed by small RNA sequencing. Genes showing fold change ≥ 1.5 and <italic>P</italic> < 0.05 were selected for depiction in a heat map, scaled from low (blue) to high (red). (B) Z138 cells were treated with DMSO (vehicle) or 10 μM nutlin-3a. After 6 h, small RNA isolated from Z138 cells using the mirVana miRNA isolation kit was subjected to RT-qPCR analysis of mature miRNA. Levels of mature miRNA were normalized to those of U6 RNA in the same sample. Data are presented as mean ± SEM. #, genes with fold change ≥ 2 were selected. (C) 293T cells were cotransfected with control vector or expression plasmid for NIK and miRNA mimic negative control (C) or 100 nM miRNA mimics. After 48 h, cell lysates were analyzed via immunoblotting. (D) H1299 cells were cotransfected with expression plasmids for NIK or p53 and miRNA inhibitor negative control (N.C.), 100 nM anti-miR-34b-5p or 100 nM anti-miR-34b-3p. After 48 h, cell lysates were analyzed via immunoblotting. (E) H1299 cells were transfected with control vector, expression plasmids for p53-WT or p53-R175H, followed by miRNA isolation and RT-qPCR analysis. Levels of miR-34b-5p were normalized to U6 RNA in the same sample. (F) Upper panels; Location of the seed binding site of miR-34b-5p was predicted at 786–792 nt of CDS of NIK. The 123 bp partial NIK-CDS containing this putative binding site was inserted into 3′ end of <italic>Firefly</italic> luciferase of pCMV-pGL3-Luciferase plasmid (Luc-NIK-WT). Mutations were generated at the seed binding site as indicated (Luc-NIK-Mut). Lower panels; H1299 cells were cotransfected with the Luc-NIK-WT or Luc-NIK-Mut reporter construct and miRNA mimic negative control (N.C.) or 100 nM miR-34b mimic and subjected to the dual luciferase assay. Activities of Luc-NIK-WT or Luc-NIK-Mut reporter were normalized to those of cotransfected CMV-Renilla construct after 48 h transfection. (G) HeLa cells were transfected with miRNA inhibitor negative control (N.C.) or 100 nM anti-miR-34b-5p. After 24 h transfection, HeLa cells were either left untreated or treated with 100 ng/ml LIGHT for the indicated time-periods. (H) Image depicting the involvement of miR-34b-induced silencing of NIK in crosstalk between the non-canonical NF-κB and p53 pathways. Quantitative data in Figures 4E and 4F represent mean ± SEM. *<italic>P</italic> < 0.05 versus the corresponding control; <sup>†</sup><italic>P</italic> < 0.05 for the indicated comparisons; ns, not significant via Student’s <italic>t</italic>-test.</p></caption><graphic xlink:href="molce-43-023f4a"></graphic><graphic xlink:href="molce-43-023f4b"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Corée du Sud</li></country></list><tree><country name="Corée du Sud"><noRegion><name sortKey="Jang, Hanbit" sort="Jang, Hanbit" uniqKey="Jang H" first="Hanbit" last="Jang">Hanbit Jang</name></noRegion><name sortKey="Cho, Sayeon" sort="Cho, Sayeon" uniqKey="Cho S" first="Sayeon" last="Cho">Sayeon Cho</name><name sortKey="Jang, Hanbit" sort="Jang, Hanbit" uniqKey="Jang H" first="Hanbit" last="Jang">Hanbit Jang</name><name sortKey="Kim, Jaehoon" sort="Kim, Jaehoon" uniqKey="Kim J" first="Jaehoon" last="Kim">Jaehoon Kim</name><name sortKey="Kim, Jeong Hoon" sort="Kim, Jeong Hoon" uniqKey="Kim J" first="Jeong-Hoon" last="Kim">Jeong-Hoon Kim</name><name sortKey="Kim, Jeong Hoon" sort="Kim, Jeong Hoon" uniqKey="Kim J" first="Jeong-Hoon" last="Kim">Jeong-Hoon Kim</name><name sortKey="Kim, Jong Hwan" sort="Kim, Jong Hwan" uniqKey="Kim J" first="Jong Hwan" last="Kim">Jong Hwan Kim</name><name sortKey="Kim, Seon Young" sort="Kim, Seon Young" uniqKey="Kim S" first="Seon-Young" last="Kim">Seon-Young Kim</name><name sortKey="Kim, Sunhong" sort="Kim, Sunhong" uniqKey="Kim S" first="Sunhong" last="Kim">Sunhong Kim</name><name sortKey="Kim, Sunhong" sort="Kim, Sunhong" uniqKey="Kim S" first="Sunhong" last="Kim">Sunhong Kim</name><name sortKey="Park, Byoung Chul" sort="Park, Byoung Chul" uniqKey="Park B" first="Byoung Chul" last="Park">Byoung Chul Park</name><name sortKey="Park, Byoung Chul" sort="Park, Byoung Chul" uniqKey="Park B" first="Byoung Chul" last="Park">Byoung Chul Park</name><name sortKey="Park, Seulki" sort="Park, Seulki" uniqKey="Park S" first="Seulki" last="Park">Seulki Park</name><name sortKey="Park, Seulki" sort="Park, Seulki" uniqKey="Park S" first="Seulki" last="Park">Seulki Park</name><name sortKey="Park, Sung Goo" sort="Park, Sung Goo" uniqKey="Park S" first="Sung Goo" last="Park">Sung Goo Park</name><name sortKey="Park, Sung Goo" sort="Park, Sung Goo" uniqKey="Park S" first="Sung Goo" last="Park">Sung Goo Park</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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