hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing
Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a...
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| Veröffentlicht in: | The Journal of clinical investigation 2010-11, Vol.120 (11), p.3923-3939 |
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| creator | Goehe, Rachel Wilson Shultz, Jacqueline C Murudkar, Charuta Usanovic, Sanja Lamour, Nadia F Massey, Davis H Zhang, Lian Camidge, D Ross Shay, Jerry W Minna, John D Chalfant, Charles E |
| description | Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells. |
| doi_str_mv | 10.1172/jci43552 |
| format | Article |
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Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci43552</identifier><identifier>PMID: 20972334</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Alternative Splicing ; Animal models ; Animals ; Apoptosis ; Biomedical research ; Caspase 9 - genetics ; Caspase 9 - metabolism ; Caspase-9 ; Cell Line, Tumor ; Exons ; Genetic aspects ; Health aspects ; Heterogeneous-Nuclear Ribonucleoprotein L - genetics ; Heterogeneous-Nuclear Ribonucleoprotein L - metabolism ; Humans ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Lung cancer ; Lung cancer, Non-small cell ; Lung Neoplasms - enzymology ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Male ; Mice ; Mice, SCID ; Neoplasm Transplantation ; Non-small cell lung carcinoma ; Phosphorylation ; Physiological aspects ; Post-transcription ; Post-translation ; Post-translational modification ; Ribonucleoproteins ; RNA Precursors - genetics ; RNA Precursors - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Silencer Elements, Transcriptional ; Splicing ; Transplantation, Heterologous ; Tumor suppressor genes ; Tumors ; Xenografts</subject><ispartof>The Journal of clinical investigation, 2010-11, Vol.120 (11), p.3923-3939</ispartof><rights>COPYRIGHT 2010 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Nov 2010</rights><rights>Copyright © 2010, American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c701t-3542eb4d6c030eb9986d343f391478a3e5bbfa5001de9474a3b8cadb68085e383</citedby><cites>FETCH-LOGICAL-c701t-3542eb4d6c030eb9986d343f391478a3e5bbfa5001de9474a3b8cadb68085e383</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/PMC2964989/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964989/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20972334$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goehe, Rachel Wilson</creatorcontrib><creatorcontrib>Shultz, Jacqueline C</creatorcontrib><creatorcontrib>Murudkar, Charuta</creatorcontrib><creatorcontrib>Usanovic, Sanja</creatorcontrib><creatorcontrib>Lamour, Nadia F</creatorcontrib><creatorcontrib>Massey, Davis H</creatorcontrib><creatorcontrib>Zhang, Lian</creatorcontrib><creatorcontrib>Camidge, D Ross</creatorcontrib><creatorcontrib>Shay, Jerry W</creatorcontrib><creatorcontrib>Minna, John D</creatorcontrib><creatorcontrib>Chalfant, Charles E</creatorcontrib><title>hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells.</description><subject>Alternative Splicing</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biomedical research</subject><subject>Caspase 9 - genetics</subject><subject>Caspase 9 - metabolism</subject><subject>Caspase-9</subject><subject>Cell Line, Tumor</subject><subject>Exons</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Heterogeneous-Nuclear Ribonucleoprotein L - genetics</subject><subject>Heterogeneous-Nuclear Ribonucleoprotein L - metabolism</subject><subject>Humans</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Lung cancer</subject><subject>Lung cancer, Non-small cell</subject><subject>Lung Neoplasms - enzymology</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Neoplasm Transplantation</subject><subject>Non-small cell lung carcinoma</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Post-transcription</subject><subject>Post-translation</subject><subject>Post-translational modification</subject><subject>Ribonucleoproteins</subject><subject>RNA Precursors - genetics</subject><subject>RNA Precursors - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Silencer Elements, Transcriptional</subject><subject>Splicing</subject><subject>Transplantation, Heterologous</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqN0luLEzEUAOBBFLeugr9AgoKXh1kzSWYmeRFK8VIpu1IvryGTnpmmzCQ1ySy7_97UrctWikgeEk6-HJKck2VPC3xWFDV5u9GG0bIk97JJUZY854Ty-9kEY1Lkoqb8JHsUwgbjgrGSPcxOCBY1oZRNMru2y_MvaIE8dGOvIgQU14DiODhvOrBGI622Spt4jVyL-tF2KWA1eHQF1nVetTEgY9FgNKBLo9Ju2KoAuUBbD_mwPJ-mhdMQgrHd4-xBq_oAT_bzafb9w_tvs0_54uLjfDZd5LrGRcxpyQg0bFVpTDE0QvBqRRltqShYzRWFsmlaVaYHrUCwminacK1WTcUxL4Fyepq9u8m7HZsBVhps9KqXW28G5a-lU0Ye7lizlp27lERUTHCRErzaJ_Du5wghysEEDX2vLLgxyLoipGa0wkm-_qcsMOG4ZgKXiT7_i27c6G36CMkZZ7jijCb04gZ1qgdpbOvSBfUup5wSRgqOidip_IhKBYP0GmehNSl84M-O-DRWkCp39MCbgwPJRLiKnRpDkPOvy_-3Fz8O7cs7dg2qj-vg-jEaZ8Mh3P-r9i4ED-1t9Qosd10vP8_mv7s-0Wd3q30L_7Q5_QWcEffB</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>Goehe, Rachel Wilson</creator><creator>Shultz, Jacqueline C</creator><creator>Murudkar, Charuta</creator><creator>Usanovic, Sanja</creator><creator>Lamour, Nadia F</creator><creator>Massey, Davis H</creator><creator>Zhang, Lian</creator><creator>Camidge, D Ross</creator><creator>Shay, Jerry W</creator><creator>Minna, John D</creator><creator>Chalfant, Charles E</creator><general>American Society for Clinical Investigation</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7TM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20101101</creationdate><title>hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing</title><author>Goehe, Rachel Wilson ; Shultz, Jacqueline C ; Murudkar, Charuta ; Usanovic, Sanja ; Lamour, Nadia F ; Massey, Davis H ; Zhang, Lian ; Camidge, D Ross ; Shay, Jerry W ; Minna, John D ; Chalfant, Charles E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c701t-3542eb4d6c030eb9986d343f391478a3e5bbfa5001de9474a3b8cadb68085e383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alternative Splicing</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biomedical research</topic><topic>Caspase 9 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Goehe, Rachel Wilson</au><au>Shultz, Jacqueline C</au><au>Murudkar, Charuta</au><au>Usanovic, Sanja</au><au>Lamour, Nadia F</au><au>Massey, Davis H</au><au>Zhang, Lian</au><au>Camidge, D Ross</au><au>Shay, Jerry W</au><au>Minna, John D</au><au>Chalfant, Charles E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2010-11-01</date><risdate>2010</risdate><volume>120</volume><issue>11</issue><spage>3923</spage><epage>3939</epage><pages>3923-3939</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>20972334</pmid><doi>10.1172/jci43552</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of clinical investigation, 2010-11, Vol.120 (11), p.3923-3939 |
| issn | 0021-9738 1558-8238 |
| language | eng |
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| source | MEDLINE; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Alternative Splicing Animal models Animals Apoptosis Biomedical research Caspase 9 - genetics Caspase 9 - metabolism Caspase-9 Cell Line, Tumor Exons Genetic aspects Health aspects Heterogeneous-Nuclear Ribonucleoprotein L - genetics Heterogeneous-Nuclear Ribonucleoprotein L - metabolism Humans Isoenzymes - genetics Isoenzymes - metabolism Lung cancer Lung cancer, Non-small cell Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - pathology Male Mice Mice, SCID Neoplasm Transplantation Non-small cell lung carcinoma Phosphorylation Physiological aspects Post-transcription Post-translation Post-translational modification Ribonucleoproteins RNA Precursors - genetics RNA Precursors - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Silencer Elements, Transcriptional Splicing Transplantation, Heterologous Tumor suppressor genes Tumors Xenografts |
| title | hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing |
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