Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA
The transcription factor NF-kappaB is activated by the degradation of its inhibitor IkappaBalpha, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediate...
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| Veröffentlicht in: | Molecular cell 2003-12, Vol.12 (6), p.1413-1426 |
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| creator | Ryo, Akihide Suizu, Futoshi Yoshida, Yasuhiro Perrem, Kilian Liou, Yih-Cherng Wulf, Gerburg Rottapel, Robert Yamaoka, Shoji Lu, Kun Ping |
| description | The transcription factor NF-kappaB is activated by the degradation of its inhibitor IkappaBalpha, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers. |
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However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.</description><identifier>ISSN: 1097-2765</identifier><identifier>PMID: 14690596</identifier><language>eng</language><publisher>United States</publisher><subject>Amino Acid Motifs ; Animals ; Binding Sites ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Carrier Proteins - metabolism ; Cells, Cultured ; Cytokines - metabolism ; DNA-Binding Proteins - metabolism ; Female ; Fibroblasts - cytology ; Fibroblasts - physiology ; Humans ; I-kappa B Kinase ; I-kappa B Proteins - metabolism ; Intracellular Signaling Peptides and Proteins ; Mice ; Mice, Knockout ; NF-kappa B - antagonists & inhibitors ; NF-kappa B - metabolism ; NF-KappaB Inhibitor alpha ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase - genetics ; Peptidylprolyl Isomerase - metabolism ; Phosphorylation ; Protein Binding ; Protein Subunits - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; Repressor Proteins - metabolism ; Signal Transduction - physiology ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins ; Transcription Factor RelA ; Transcriptional Activation ; Ubiquitin - metabolism</subject><ispartof>Molecular cell, 2003-12, Vol.12 (6), p.1413-1426</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14690596$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ryo, Akihide</creatorcontrib><creatorcontrib>Suizu, Futoshi</creatorcontrib><creatorcontrib>Yoshida, Yasuhiro</creatorcontrib><creatorcontrib>Perrem, Kilian</creatorcontrib><creatorcontrib>Liou, Yih-Cherng</creatorcontrib><creatorcontrib>Wulf, Gerburg</creatorcontrib><creatorcontrib>Rottapel, Robert</creatorcontrib><creatorcontrib>Yamaoka, Shoji</creatorcontrib><creatorcontrib>Lu, Kun Ping</creatorcontrib><title>Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>The transcription factor NF-kappaB is activated by the degradation of its inhibitor IkappaBalpha, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.</description><subject>Amino Acid Motifs</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Carrier Proteins - metabolism</subject><subject>Cells, Cultured</subject><subject>Cytokines - metabolism</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Female</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - physiology</subject><subject>Humans</subject><subject>I-kappa B Kinase</subject><subject>I-kappa B Proteins - metabolism</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>NF-kappa B - antagonists & inhibitors</subject><subject>NF-kappa B - metabolism</subject><subject>NF-KappaB Inhibitor alpha</subject><subject>NIMA-Interacting Peptidylprolyl Isomerase</subject><subject>Peptidylprolyl Isomerase - genetics</subject><subject>Peptidylprolyl Isomerase - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein Subunits - metabolism</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Repressor Proteins - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Suppressor of Cytokine Signaling 1 Protein</subject><subject>Suppressor of Cytokine Signaling Proteins</subject><subject>Transcription Factor RelA</subject><subject>Transcriptional Activation</subject><subject>Ubiquitin - metabolism</subject><issn>1097-2765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kDFPwzAQhT2AaCn8BeSJLcKJYyceS0UBqQJUdY_s-FwZHMeNE6Hy63FVGO7d8t27d3eB5jkRVVZUnM3QdYyfhOQlq8UVmuUlF4QJPkffW9hPTo6297g3-G2dfckQ5COOdu-ls36P1RF_WJ9nGgJ4DX7EYejd0WEb-w4G-3Oell7jSdnDZEfrsw60lSPoEztCwqONpwWBs4ctuOUNujTSRbj96wu0Wz_tVi_Z5v35dbXcZIGVPJOUE2MK0moGnFGuUhmV19SolgIpFK11YdIxLW2VoCIpzTXRwoDhRki6QPdn2xTjMEEcm87GFpyTHvopNlVe1rwq6gTe_YGTStmbMNhODsfm_1P0F0sXZi0</recordid><startdate>200312</startdate><enddate>200312</enddate><creator>Ryo, Akihide</creator><creator>Suizu, Futoshi</creator><creator>Yoshida, Yasuhiro</creator><creator>Perrem, Kilian</creator><creator>Liou, Yih-Cherng</creator><creator>Wulf, Gerburg</creator><creator>Rottapel, Robert</creator><creator>Yamaoka, Shoji</creator><creator>Lu, Kun Ping</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>200312</creationdate><title>Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA</title><author>Ryo, Akihide ; Suizu, Futoshi ; Yoshida, Yasuhiro ; Perrem, Kilian ; Liou, Yih-Cherng ; Wulf, Gerburg ; Rottapel, Robert ; Yamaoka, Shoji ; Lu, Kun Ping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p546-a360ff20cd5e6536b536fb183fbc3e02b38d2f469c3cb9393cb31d0d9fef6f9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Amino Acid Motifs</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Carrier Proteins - metabolism</topic><topic>Cells, Cultured</topic><topic>Cytokines - metabolism</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Female</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - physiology</topic><topic>Humans</topic><topic>I-kappa B Kinase</topic><topic>I-kappa B Proteins - metabolism</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>NF-kappa B - antagonists & inhibitors</topic><topic>NF-kappa B - metabolism</topic><topic>NF-KappaB Inhibitor alpha</topic><topic>NIMA-Interacting Peptidylprolyl Isomerase</topic><topic>Peptidylprolyl Isomerase - genetics</topic><topic>Peptidylprolyl Isomerase - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein Subunits - metabolism</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Repressor Proteins - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Suppressor of Cytokine Signaling 1 Protein</topic><topic>Suppressor of Cytokine Signaling Proteins</topic><topic>Transcription Factor RelA</topic><topic>Transcriptional Activation</topic><topic>Ubiquitin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ryo, Akihide</creatorcontrib><creatorcontrib>Suizu, Futoshi</creatorcontrib><creatorcontrib>Yoshida, Yasuhiro</creatorcontrib><creatorcontrib>Perrem, Kilian</creatorcontrib><creatorcontrib>Liou, Yih-Cherng</creatorcontrib><creatorcontrib>Wulf, Gerburg</creatorcontrib><creatorcontrib>Rottapel, Robert</creatorcontrib><creatorcontrib>Yamaoka, Shoji</creatorcontrib><creatorcontrib>Lu, Kun Ping</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ryo, Akihide</au><au>Suizu, Futoshi</au><au>Yoshida, Yasuhiro</au><au>Perrem, Kilian</au><au>Liou, Yih-Cherng</au><au>Wulf, Gerburg</au><au>Rottapel, Robert</au><au>Yamaoka, Shoji</au><au>Lu, Kun Ping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2003-12</date><risdate>2003</risdate><volume>12</volume><issue>6</issue><spage>1413</spage><epage>1426</epage><pages>1413-1426</pages><issn>1097-2765</issn><abstract>The transcription factor NF-kappaB is activated by the degradation of its inhibitor IkappaBalpha, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.</abstract><cop>United States</cop><pmid>14690596</pmid><tpages>14</tpages></addata></record> |
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| subjects | Amino Acid Motifs Animals Binding Sites Breast Neoplasms - metabolism Breast Neoplasms - pathology Carrier Proteins - metabolism Cells, Cultured Cytokines - metabolism DNA-Binding Proteins - metabolism Female Fibroblasts - cytology Fibroblasts - physiology Humans I-kappa B Kinase I-kappa B Proteins - metabolism Intracellular Signaling Peptides and Proteins Mice Mice, Knockout NF-kappa B - antagonists & inhibitors NF-kappa B - metabolism NF-KappaB Inhibitor alpha NIMA-Interacting Peptidylprolyl Isomerase Peptidylprolyl Isomerase - genetics Peptidylprolyl Isomerase - metabolism Phosphorylation Protein Binding Protein Subunits - metabolism Protein-Serine-Threonine Kinases - metabolism Repressor Proteins - metabolism Signal Transduction - physiology Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins Transcription Factor RelA Transcriptional Activation Ubiquitin - metabolism |
| title | Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA |
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