A Truncated Form of p23 Down-regulates Telomerase Activity via Disruption of Hsp90 Function
The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins. Previous reports indicate that p23 cleavage induced by caspases during cell death triggers destabilization of client proteins. However, the specific...
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| Veröffentlicht in: | The Journal of biological chemistry 2009-11, Vol.284 (45), p.30871-30880 |
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| creator | Woo, Sang Hyeok An, Sungkwan Lee, Hyung-Chahn Jin, Hyeon-Ok Seo, Sung-Keum Yoo, Doo-Hyun Lee, Kee-Ho Rhee, Chang Hun Choi, Eui-Ju Hong, Seok-Il Park, In-Chul |
| description | The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins. Previous reports indicate that p23 cleavage induced by caspases during cell death triggers destabilization of client proteins. However, the specific role of truncated p23 (Δp23) in this process and the underlying mechanisms remain to be determined. One such client protein, hTERT, is a telomerase catalytic subunit regulated by several chaperone proteins, including Hsp90 and p23. In the present study, we examined the effects of p23 cleavage on hTERT stability and telomerase activity. Our data showed that overexpression of Δp23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity. Serine phosphorylation of Hsp90 was significantly reduced in cells expressing high levels of Δp23 compared with those expressing full-length p23. Mutation analyses revealed that two serine residues (Ser-231 and Ser-263) in Hsp90 are important for activation of telomerase, and down-regulation of telomerase activity by Δp23 was associated with inhibition of cell growth and sensitization of cells to cisplatin. Our data aid in determining the mechanism underlying the regulation of telomerase activity by the chaperone complex during caspase-dependent cell death. |
| doi_str_mv | 10.1074/jbc.M109.052720 |
| format | Article |
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Previous reports indicate that p23 cleavage induced by caspases during cell death triggers destabilization of client proteins. However, the specific role of truncated p23 (Δp23) in this process and the underlying mechanisms remain to be determined. One such client protein, hTERT, is a telomerase catalytic subunit regulated by several chaperone proteins, including Hsp90 and p23. In the present study, we examined the effects of p23 cleavage on hTERT stability and telomerase activity. Our data showed that overexpression of Δp23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity. Serine phosphorylation of Hsp90 was significantly reduced in cells expressing high levels of Δp23 compared with those expressing full-length p23. Mutation analyses revealed that two serine residues (Ser-231 and Ser-263) in Hsp90 are important for activation of telomerase, and down-regulation of telomerase activity by Δp23 was associated with inhibition of cell growth and sensitization of cells to cisplatin. Our data aid in determining the mechanism underlying the regulation of telomerase activity by the chaperone complex during caspase-dependent cell death.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M109.052720</identifier><identifier>PMID: 19740745</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cell Line ; DNA-Binding Proteins - chemistry ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Down-Regulation ; HSP90 Heat-Shock Proteins - genetics ; HSP90 Heat-Shock Proteins - metabolism ; Humans ; Phosphorylation ; Protein Stability ; Protein Synthesis, Post-Translational Modification, and Degradation ; Telomerase - genetics ; Telomerase - metabolism</subject><ispartof>The Journal of biological chemistry, 2009-11, Vol.284 (45), p.30871-30880</ispartof><rights>2009 © 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2009 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-c502t-424768c95e20132dcaa5404bccf799e798d8e5961d5bbe93bfa87873c275cdd3</citedby><cites>FETCH-LOGICAL-c502t-424768c95e20132dcaa5404bccf799e798d8e5961d5bbe93bfa87873c275cdd3</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/PMC2781486/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781486/$$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/19740745$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Woo, Sang Hyeok</creatorcontrib><creatorcontrib>An, Sungkwan</creatorcontrib><creatorcontrib>Lee, Hyung-Chahn</creatorcontrib><creatorcontrib>Jin, Hyeon-Ok</creatorcontrib><creatorcontrib>Seo, Sung-Keum</creatorcontrib><creatorcontrib>Yoo, Doo-Hyun</creatorcontrib><creatorcontrib>Lee, Kee-Ho</creatorcontrib><creatorcontrib>Rhee, Chang Hun</creatorcontrib><creatorcontrib>Choi, Eui-Ju</creatorcontrib><creatorcontrib>Hong, Seok-Il</creatorcontrib><creatorcontrib>Park, In-Chul</creatorcontrib><title>A Truncated Form of p23 Down-regulates Telomerase Activity via Disruption of Hsp90 Function</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins. Previous reports indicate that p23 cleavage induced by caspases during cell death triggers destabilization of client proteins. However, the specific role of truncated p23 (Δp23) in this process and the underlying mechanisms remain to be determined. One such client protein, hTERT, is a telomerase catalytic subunit regulated by several chaperone proteins, including Hsp90 and p23. In the present study, we examined the effects of p23 cleavage on hTERT stability and telomerase activity. Our data showed that overexpression of Δp23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity. Serine phosphorylation of Hsp90 was significantly reduced in cells expressing high levels of Δp23 compared with those expressing full-length p23. Mutation analyses revealed that two serine residues (Ser-231 and Ser-263) in Hsp90 are important for activation of telomerase, and down-regulation of telomerase activity by Δp23 was associated with inhibition of cell growth and sensitization of cells to cisplatin. Our data aid in determining the mechanism underlying the regulation of telomerase activity by the chaperone complex during caspase-dependent cell death.</description><subject>Cell Line</subject><subject>DNA-Binding Proteins - chemistry</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Down-Regulation</subject><subject>HSP90 Heat-Shock Proteins - genetics</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Phosphorylation</subject><subject>Protein Stability</subject><subject>Protein Synthesis, Post-Translational Modification, and Degradation</subject><subject>Telomerase - genetics</subject><subject>Telomerase - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-P1CAcxYnRuOPq2ZvhYPTUWaAwwMVksuu4Jmu8zMHEA6H02xk2banQzmb_e2k68cdBuZDw_byX9-Uh9JqSNSWSX91Xbv2FEr0mgklGnqAVJaosSkG_PUUrQhgtNBPqAr1I6Z7kwzV9ji6oljzLxQp93-J9nHpnR6jxLsQOhwYPrMQ34aEvIhymNo8S3kMbOog2Ad660Z_8-IhP3uIbn-I0jD70s_A2DZrgXfabX16iZ41tE7w635dov_u4v74t7r5--ny9vSucIGwsOONyo5wWwAgtWe2sFZzwyrlGag1Sq1qB0Btai6oCXVaNVVLJ0jEpXF2Xl-jDYjtMVQe1g36MtjVD9J2NjyZYb_6e9P5oDuFkmFSUq002eH82iOHHBGk0nU8O2tb2EKZkZMkplUTRTL77L8kyJwRTGbxaQBdDShGaX3EoMXNzJjdn5ubM0lxWvPlzi9_8uaoMvF2Aoz8cH3wEU_ngjtAZprjhwpREyTmiXjDIP37yEE1yHnoHdZa40dTB_zPDTyUwtAM</recordid><startdate>20091106</startdate><enddate>20091106</enddate><creator>Woo, Sang Hyeok</creator><creator>An, Sungkwan</creator><creator>Lee, Hyung-Chahn</creator><creator>Jin, Hyeon-Ok</creator><creator>Seo, Sung-Keum</creator><creator>Yoo, Doo-Hyun</creator><creator>Lee, Kee-Ho</creator><creator>Rhee, Chang Hun</creator><creator>Choi, Eui-Ju</creator><creator>Hong, Seok-Il</creator><creator>Park, In-Chul</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20091106</creationdate><title>A Truncated Form of p23 Down-regulates Telomerase Activity via Disruption of Hsp90 Function</title><author>Woo, Sang Hyeok ; An, Sungkwan ; Lee, Hyung-Chahn ; Jin, Hyeon-Ok ; Seo, Sung-Keum ; Yoo, Doo-Hyun ; Lee, Kee-Ho ; Rhee, Chang Hun ; Choi, Eui-Ju ; Hong, Seok-Il ; Park, In-Chul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-424768c95e20132dcaa5404bccf799e798d8e5961d5bbe93bfa87873c275cdd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Cell Line</topic><topic>DNA-Binding Proteins - chemistry</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Down-Regulation</topic><topic>HSP90 Heat-Shock Proteins - genetics</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Phosphorylation</topic><topic>Protein Stability</topic><topic>Protein Synthesis, Post-Translational Modification, and Degradation</topic><topic>Telomerase - genetics</topic><topic>Telomerase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Woo, Sang Hyeok</creatorcontrib><creatorcontrib>An, Sungkwan</creatorcontrib><creatorcontrib>Lee, Hyung-Chahn</creatorcontrib><creatorcontrib>Jin, Hyeon-Ok</creatorcontrib><creatorcontrib>Seo, Sung-Keum</creatorcontrib><creatorcontrib>Yoo, Doo-Hyun</creatorcontrib><creatorcontrib>Lee, Kee-Ho</creatorcontrib><creatorcontrib>Rhee, Chang Hun</creatorcontrib><creatorcontrib>Choi, Eui-Ju</creatorcontrib><creatorcontrib>Hong, Seok-Il</creatorcontrib><creatorcontrib>Park, In-Chul</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</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>Woo, Sang Hyeok</au><au>An, Sungkwan</au><au>Lee, Hyung-Chahn</au><au>Jin, Hyeon-Ok</au><au>Seo, Sung-Keum</au><au>Yoo, Doo-Hyun</au><au>Lee, Kee-Ho</au><au>Rhee, Chang Hun</au><au>Choi, Eui-Ju</au><au>Hong, Seok-Il</au><au>Park, In-Chul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Truncated Form of p23 Down-regulates Telomerase Activity via Disruption of Hsp90 Function</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2009-11-06</date><risdate>2009</risdate><volume>284</volume><issue>45</issue><spage>30871</spage><epage>30880</epage><pages>30871-30880</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins. 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Mutation analyses revealed that two serine residues (Ser-231 and Ser-263) in Hsp90 are important for activation of telomerase, and down-regulation of telomerase activity by Δp23 was associated with inhibition of cell growth and sensitization of cells to cisplatin. Our data aid in determining the mechanism underlying the regulation of telomerase activity by the chaperone complex during caspase-dependent cell death.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19740745</pmid><doi>10.1074/jbc.M109.052720</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Cell Line DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Down-Regulation HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Humans Phosphorylation Protein Stability Protein Synthesis, Post-Translational Modification, and Degradation Telomerase - genetics Telomerase - metabolism |
| title | A Truncated Form of p23 Down-regulates Telomerase Activity via Disruption of Hsp90 Function |
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