SENP1 deSUMOylates and Regulates Pin1 Protein Activity and Cellular Function
The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activit...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (13), p.3951-3962 |
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| creator | CHEN, Chun-Hau CHANG, Che-Chang SHIH, Hsiu-Ming KUN PING LU TAE HO LEE MANLI LUO PENGYU HUANG LIAO, Pei-Hsin SHUO WEI LI, Fu-An CHEN, Ruey-Hwa XIAO ZHEN ZHOU |
| description | The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis. |
| doi_str_mv | 10.1158/0008-5472.can-12-4360 |
| format | Article |
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SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-12-4360</identifier><identifier>PMID: 23633483</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Breast Neoplasms - enzymology ; Cell Line ; Cell Transformation, Neoplastic - metabolism ; Centrosome - metabolism ; Chromosomal Instability ; Cyclin D1 ; Cysteine Endopeptidases ; Endopeptidases - metabolism ; Female ; Gene Knockdown Techniques ; Humans ; Medical sciences ; Mice ; NIMA-Interacting Peptidylprolyl Isomerase ; Oxidative Stress ; Peptidylprolyl Isomerase - chemistry ; Peptidylprolyl Isomerase - genetics ; Peptidylprolyl Isomerase - metabolism ; Pharmacology. Drug treatments ; Protein Binding ; Protein Interaction Domains and Motifs ; Signal Transduction ; Sumoylation ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2013-07, Vol.73 (13), p.3951-3962</ispartof><rights>2014 INIST-CNRS</rights><rights>2013 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c507t-860ada3b9dcb58912b5b076ca896bb65d817c0d0d74bc5fbb1516b5b927afcf83</citedby><cites>FETCH-LOGICAL-c507t-860ada3b9dcb58912b5b076ca896bb65d817c0d0d74bc5fbb1516b5b927afcf83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27502017$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23633483$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CHEN, Chun-Hau</creatorcontrib><creatorcontrib>CHANG, Che-Chang</creatorcontrib><creatorcontrib>SHIH, Hsiu-Ming</creatorcontrib><creatorcontrib>KUN PING LU</creatorcontrib><creatorcontrib>TAE HO LEE</creatorcontrib><creatorcontrib>MANLI LUO</creatorcontrib><creatorcontrib>PENGYU HUANG</creatorcontrib><creatorcontrib>LIAO, Pei-Hsin</creatorcontrib><creatorcontrib>SHUO WEI</creatorcontrib><creatorcontrib>LI, Fu-An</creatorcontrib><creatorcontrib>CHEN, Ruey-Hwa</creatorcontrib><creatorcontrib>XIAO ZHEN ZHOU</creatorcontrib><title>SENP1 deSUMOylates and Regulates Pin1 Protein Activity and Cellular Function</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis.</description><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - enzymology</subject><subject>Cell Line</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Centrosome - metabolism</subject><subject>Chromosomal Instability</subject><subject>Cyclin D1</subject><subject>Cysteine Endopeptidases</subject><subject>Endopeptidases - metabolism</subject><subject>Female</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>NIMA-Interacting Peptidylprolyl Isomerase</subject><subject>Oxidative Stress</subject><subject>Peptidylprolyl Isomerase - chemistry</subject><subject>Peptidylprolyl Isomerase - genetics</subject><subject>Peptidylprolyl Isomerase - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Binding</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Signal Transduction</subject><subject>Sumoylation</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkNFOwjAUhhujEUQfQbMbL4c967p2NyaEgJogEJHrpu06rBkdWQcJb-8miHp1ck6__2_yIXQLuA9A-QPGmIc0ZlFfSxdCFMYkwWeoC5TwkMUxPUfdE9NBV95_NisFTC9RJyIJITEnXTRZjKZzCDKzWL7O9oWsjQ-ky4I3s9oetrl1EMyrsjbWBQNd252t99_M0BRFA1XBeOuae-mu0UUuC29ujrOHluPR-_A5nMyeXoaDSagpZnXIEywzSVSaaUV5CpGiCrNES54mSiU048A0znDGYqVprhRQSBomjZjMdc5JDz0eejdbtTaZNq6uZCE2lV3Lai9KacX_F2c_xKrcCcKBQwRNAT0U6Kr0vjL5KQtYtHpFq0606sRwMBUQiVZvk7v7-_Ep9eOzAe6PgPRaFnklnbb-l2MURxgY-QJfh4R1</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>CHEN, Chun-Hau</creator><creator>CHANG, Che-Chang</creator><creator>SHIH, Hsiu-Ming</creator><creator>KUN PING LU</creator><creator>TAE HO LEE</creator><creator>MANLI LUO</creator><creator>PENGYU HUANG</creator><creator>LIAO, Pei-Hsin</creator><creator>SHUO WEI</creator><creator>LI, Fu-An</creator><creator>CHEN, Ruey-Hwa</creator><creator>XIAO ZHEN ZHOU</creator><general>American Association for Cancer Research</general><scope>IQODW</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>5PM</scope></search><sort><creationdate>20130701</creationdate><title>SENP1 deSUMOylates and Regulates Pin1 Protein Activity and Cellular Function</title><author>CHEN, Chun-Hau ; CHANG, Che-Chang ; SHIH, Hsiu-Ming ; KUN PING LU ; TAE HO LEE ; MANLI LUO ; PENGYU HUANG ; LIAO, Pei-Hsin ; SHUO WEI ; LI, Fu-An ; CHEN, Ruey-Hwa ; XIAO ZHEN ZHOU</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c507t-860ada3b9dcb58912b5b076ca896bb65d817c0d0d74bc5fbb1516b5b927afcf83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - enzymology</topic><topic>Cell Line</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Centrosome - metabolism</topic><topic>Chromosomal Instability</topic><topic>Cyclin D1</topic><topic>Cysteine Endopeptidases</topic><topic>Endopeptidases - metabolism</topic><topic>Female</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>NIMA-Interacting Peptidylprolyl Isomerase</topic><topic>Oxidative Stress</topic><topic>Peptidylprolyl Isomerase - chemistry</topic><topic>Peptidylprolyl Isomerase - genetics</topic><topic>Peptidylprolyl Isomerase - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Binding</topic><topic>Protein Interaction Domains and Motifs</topic><topic>Signal Transduction</topic><topic>Sumoylation</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHEN, Chun-Hau</creatorcontrib><creatorcontrib>CHANG, Che-Chang</creatorcontrib><creatorcontrib>SHIH, Hsiu-Ming</creatorcontrib><creatorcontrib>KUN PING LU</creatorcontrib><creatorcontrib>TAE HO LEE</creatorcontrib><creatorcontrib>MANLI LUO</creatorcontrib><creatorcontrib>PENGYU HUANG</creatorcontrib><creatorcontrib>LIAO, Pei-Hsin</creatorcontrib><creatorcontrib>SHUO WEI</creatorcontrib><creatorcontrib>LI, Fu-An</creatorcontrib><creatorcontrib>CHEN, Ruey-Hwa</creatorcontrib><creatorcontrib>XIAO ZHEN ZHOU</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHEN, Chun-Hau</au><au>CHANG, Che-Chang</au><au>SHIH, Hsiu-Ming</au><au>KUN PING LU</au><au>TAE HO LEE</au><au>MANLI LUO</au><au>PENGYU HUANG</au><au>LIAO, Pei-Hsin</au><au>SHUO WEI</au><au>LI, Fu-An</au><au>CHEN, Ruey-Hwa</au><au>XIAO ZHEN ZHOU</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SENP1 deSUMOylates and Regulates Pin1 Protein Activity and Cellular Function</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>73</volume><issue>13</issue><spage>3951</spage><epage>3962</epage><pages>3951-3962</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>23633483</pmid><doi>10.1158/0008-5472.can-12-4360</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2013-07, Vol.73 (13), p.3951-3962 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Amino Acid Sequence Amino Acid Substitution Animals Antineoplastic agents Biological and medical sciences Breast Neoplasms - enzymology Cell Line Cell Transformation, Neoplastic - metabolism Centrosome - metabolism Chromosomal Instability Cyclin D1 Cysteine Endopeptidases Endopeptidases - metabolism Female Gene Knockdown Techniques Humans Medical sciences Mice NIMA-Interacting Peptidylprolyl Isomerase Oxidative Stress Peptidylprolyl Isomerase - chemistry Peptidylprolyl Isomerase - genetics Peptidylprolyl Isomerase - metabolism Pharmacology. Drug treatments Protein Binding Protein Interaction Domains and Motifs Signal Transduction Sumoylation Tumors |
| title | SENP1 deSUMOylates and Regulates Pin1 Protein Activity and Cellular Function |
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