A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4
The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), regulates numerous biological processes, including proliferation, differentiation, and embryonic stem cell self-renewal. Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcriptio...
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| Veröffentlicht in: | The Journal of biological chemistry 2010-09, Vol.285 (36), p.28298-28308 |
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| description | The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), regulates numerous biological processes, including proliferation, differentiation, and embryonic stem cell self-renewal. Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcription is not well defined. Small ubiquitin-related modifier (SUMO) is an important regulator of transcription. Here we show that KLF4 is both SUMOylated at a single lysine residue and physically interacts with SUMO-1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus. The SIM in KLF4 is required for transactivation of target promoters in a SUMO-1-dependent manner. Mutation of either the acidic or hydrophobic residues in the SIM significantly impairs the ability of KLF4 to interact with SUMO-1, activate transcription, and inhibit cell proliferation. Our study provides direct evidence that SIM in KLF4 functions as a transcriptional activation domain. A survey of transcription factor sequences reveals that established transactivation domains of many transcription factors contain sequences highly related to SIM. These results, therefore, illustrate a novel mechanism by which SUMO interaction modulates the activity of transcription factors. |
| doi_str_mv | 10.1074/jbc.M110.101717 |
| format | Article |
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Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcription is not well defined. Small ubiquitin-related modifier (SUMO) is an important regulator of transcription. Here we show that KLF4 is both SUMOylated at a single lysine residue and physically interacts with SUMO-1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus. The SIM in KLF4 is required for transactivation of target promoters in a SUMO-1-dependent manner. Mutation of either the acidic or hydrophobic residues in the SIM significantly impairs the ability of KLF4 to interact with SUMO-1, activate transcription, and inhibit cell proliferation. Our study provides direct evidence that SIM in KLF4 functions as a transcriptional activation domain. A survey of transcription factor sequences reveals that established transactivation domains of many transcription factors contain sequences highly related to SIM. These results, therefore, illustrate a novel mechanism by which SUMO interaction modulates the activity of transcription factors.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.101717</identifier><identifier>PMID: 20584900</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Binding Sites ; Cattle ; Cell Line ; Cell Proliferation ; Chlorocebus aethiops ; COS Cells ; Gene Knockdown Techniques ; Gene Regulation ; Humans ; KLF4 ; Kruppel-Like Transcription Factors - chemistry ; Kruppel-Like Transcription Factors - metabolism ; Lysine ; Mice ; Molecular Sequence Data ; Promoters ; Protein Domains ; Protein Structure, Tertiary ; Protein Synthesis and Degradation ; Protein-Protein Interactions ; Rats ; RNA, Small Interfering - genetics ; SIM ; SUMO ; SUMO-1 Protein - deficiency ; SUMO-1 Protein - genetics ; SUMO-1 Protein - metabolism ; Transactivation ; Transcription Factor ; Transcription Regulation ; Transcriptional Activation ; Yeast</subject><ispartof>The Journal of biological chemistry, 2010-09, Vol.285 (36), p.28298-28308</ispartof><rights>2010 © 2010 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2010 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-f731f6e9bba8d727103de4538d1461315bc8660f127fe16e03e9cfbf6729a0333</citedby><cites>FETCH-LOGICAL-c466t-f731f6e9bba8d727103de4538d1461315bc8660f127fe16e03e9cfbf6729a0333</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934694/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934694/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20584900$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Du, James X.</creatorcontrib><creatorcontrib>McConnell, Beth B.</creatorcontrib><creatorcontrib>Yang, Vincent W.</creatorcontrib><title>A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), regulates numerous biological processes, including proliferation, differentiation, and embryonic stem cell self-renewal. Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcription is not well defined. Small ubiquitin-related modifier (SUMO) is an important regulator of transcription. Here we show that KLF4 is both SUMOylated at a single lysine residue and physically interacts with SUMO-1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus. The SIM in KLF4 is required for transactivation of target promoters in a SUMO-1-dependent manner. Mutation of either the acidic or hydrophobic residues in the SIM significantly impairs the ability of KLF4 to interact with SUMO-1, activate transcription, and inhibit cell proliferation. Our study provides direct evidence that SIM in KLF4 functions as a transcriptional activation domain. A survey of transcription factor sequences reveals that established transactivation domains of many transcription factors contain sequences highly related to SIM. These results, therefore, illustrate a novel mechanism by which SUMO interaction modulates the activity of transcription factors.</description><subject>Amino Acid Motifs</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Cattle</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Chlorocebus aethiops</subject><subject>COS Cells</subject><subject>Gene Knockdown Techniques</subject><subject>Gene Regulation</subject><subject>Humans</subject><subject>KLF4</subject><subject>Kruppel-Like Transcription Factors - chemistry</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Lysine</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Promoters</subject><subject>Protein Domains</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Synthesis and Degradation</subject><subject>Protein-Protein Interactions</subject><subject>Rats</subject><subject>RNA, Small Interfering - genetics</subject><subject>SIM</subject><subject>SUMO</subject><subject>SUMO-1 Protein - deficiency</subject><subject>SUMO-1 Protein - genetics</subject><subject>SUMO-1 Protein - metabolism</subject><subject>Transactivation</subject><subject>Transcription Factor</subject><subject>Transcription Regulation</subject><subject>Transcriptional Activation</subject><subject>Yeast</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kTtvFDEUhS0EIkugpgN3VJP4Mc8GaZWwJCIRRbISneXxXG8cPPbEnlmJkv9Fxx-LJxMiKHBj3XuPz7Huh9BbSo4oqfLj21YdXdKHila0eoZWlNQ84wX99hytCGE0a1hRH6BXMd6SdPKGvkQHjBR13hCyQj_X-KqX1uJta-4mMxqXBbByhA5f-s5oAyEzboQgVZrtUnM0Gm8ml0rvIpYRjzeAr4N0UQUzzF1p8TqN93Iu8KnvpXHYa_wl_P41DGAza74D3iRHH3D-Gr3Q0kZ483gfou3m0_XJWXbx9fP5yfoiU3lZjpmuONUlNG0r665iFSW8g7zgdUfzknJatKouS6IpqzTQEgiHRulWlxVrJOGcH6KPi-8wtT10CtwYpBVDML0MP4SXRvw7ceZG7PxesIbnZZMngw-PBsHfTRBH0ZuowFrpwE9RVGmjlCcqSXm8KFXwMQbQTymUiJmbSNzEzE0s3NKLd39_7kn_B1QSvF8EWnohd8FEsb1icx6ta1azWdEsCkhL3CduIioDTkFnAqhRdN78N_4ejz-zbA</recordid><startdate>20100903</startdate><enddate>20100903</enddate><creator>Du, James X.</creator><creator>McConnell, Beth B.</creator><creator>Yang, Vincent W.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100903</creationdate><title>A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4</title><author>Du, James X. ; McConnell, Beth B. ; Yang, Vincent W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-f731f6e9bba8d727103de4538d1461315bc8660f127fe16e03e9cfbf6729a0333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino Acid Motifs</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Cattle</topic><topic>Cell Line</topic><topic>Cell Proliferation</topic><topic>Chlorocebus aethiops</topic><topic>COS Cells</topic><topic>Gene Knockdown Techniques</topic><topic>Gene Regulation</topic><topic>Humans</topic><topic>KLF4</topic><topic>Kruppel-Like Transcription Factors - chemistry</topic><topic>Kruppel-Like Transcription Factors - metabolism</topic><topic>Lysine</topic><topic>Mice</topic><topic>Molecular Sequence Data</topic><topic>Promoters</topic><topic>Protein Domains</topic><topic>Protein Structure, Tertiary</topic><topic>Protein Synthesis and Degradation</topic><topic>Protein-Protein Interactions</topic><topic>Rats</topic><topic>RNA, Small Interfering - genetics</topic><topic>SIM</topic><topic>SUMO</topic><topic>SUMO-1 Protein - deficiency</topic><topic>SUMO-1 Protein - genetics</topic><topic>SUMO-1 Protein - metabolism</topic><topic>Transactivation</topic><topic>Transcription Factor</topic><topic>Transcription Regulation</topic><topic>Transcriptional Activation</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Du, James X.</creatorcontrib><creatorcontrib>McConnell, Beth B.</creatorcontrib><creatorcontrib>Yang, Vincent W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Du, James X.</au><au>McConnell, Beth B.</au><au>Yang, Vincent W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2010-09-03</date><risdate>2010</risdate><volume>285</volume><issue>36</issue><spage>28298</spage><epage>28308</epage><pages>28298-28308</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), regulates numerous biological processes, including proliferation, differentiation, and embryonic stem cell self-renewal. Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcription is not well defined. Small ubiquitin-related modifier (SUMO) is an important regulator of transcription. Here we show that KLF4 is both SUMOylated at a single lysine residue and physically interacts with SUMO-1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus. The SIM in KLF4 is required for transactivation of target promoters in a SUMO-1-dependent manner. Mutation of either the acidic or hydrophobic residues in the SIM significantly impairs the ability of KLF4 to interact with SUMO-1, activate transcription, and inhibit cell proliferation. Our study provides direct evidence that SIM in KLF4 functions as a transcriptional activation domain. A survey of transcription factor sequences reveals that established transactivation domains of many transcription factors contain sequences highly related to SIM. 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| subjects | Amino Acid Motifs Amino Acid Sequence Animals Binding Sites Cattle Cell Line Cell Proliferation Chlorocebus aethiops COS Cells Gene Knockdown Techniques Gene Regulation Humans KLF4 Kruppel-Like Transcription Factors - chemistry Kruppel-Like Transcription Factors - metabolism Lysine Mice Molecular Sequence Data Promoters Protein Domains Protein Structure, Tertiary Protein Synthesis and Degradation Protein-Protein Interactions Rats RNA, Small Interfering - genetics SIM SUMO SUMO-1 Protein - deficiency SUMO-1 Protein - genetics SUMO-1 Protein - metabolism Transactivation Transcription Factor Transcription Regulation Transcriptional Activation Yeast |
| title | A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4 |
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