RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein
RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of...
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| Veröffentlicht in: | Molecular cell 2007-09, Vol.27 (6), p.962-975 |
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| container_title | Molecular cell |
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| creator | Matallanas, David Romano, David Yee, Karen Meissl, Katrin Kucerova, Lucia Piazzolla, Daniela Baccarini, Manuela Vass, J. Keith Kolch, Walter O'Neill, Eric |
| description | RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene
puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73. |
| doi_str_mv | 10.1016/j.molcel.2007.08.008 |
| format | Article |
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puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2007.08.008</identifier><identifier>PMID: 17889669</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Apoptosis ; Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - metabolism ; Cell Line, Tumor ; Cell Nucleus - metabolism ; CELLCYCLE ; DNA-Binding Proteins - metabolism ; Humans ; Models, Biological ; Nuclear Proteins - metabolism ; Phosphoproteins - metabolism ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases - metabolism ; Protein Transport ; Proto-Oncogene Mas ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-raf - metabolism ; Serine-Threonine Kinase 3 ; Signal Transduction ; SIGNALING ; Transcription Factors ; Transcription, Genetic ; Tumor Protein p73 ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism ; YAP-Signaling Proteins</subject><ispartof>Molecular cell, 2007-09, Vol.27 (6), p.962-975</ispartof><rights>2007 Elsevier Inc.</rights><rights>2007 Elsevier Inc. 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4428-73160e034fba358508302567e217f9a4d5134000ce28076a628b4ff11b2d11d53</citedby><cites>FETCH-LOGICAL-c4428-73160e034fba358508302567e217f9a4d5134000ce28076a628b4ff11b2d11d53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2007.08.008$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17889669$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matallanas, David</creatorcontrib><creatorcontrib>Romano, David</creatorcontrib><creatorcontrib>Yee, Karen</creatorcontrib><creatorcontrib>Meissl, Katrin</creatorcontrib><creatorcontrib>Kucerova, Lucia</creatorcontrib><creatorcontrib>Piazzolla, Daniela</creatorcontrib><creatorcontrib>Baccarini, Manuela</creatorcontrib><creatorcontrib>Vass, J. Keith</creatorcontrib><creatorcontrib>Kolch, Walter</creatorcontrib><creatorcontrib>O'Neill, Eric</creatorcontrib><title>RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene
puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Nucleus - metabolism</subject><subject>CELLCYCLE</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Models, Biological</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Protein Transport</subject><subject>Proto-Oncogene Mas</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-raf - metabolism</subject><subject>Serine-Threonine Kinase 3</subject><subject>Signal Transduction</subject><subject>SIGNALING</subject><subject>Transcription Factors</subject><subject>Transcription, Genetic</subject><subject>Tumor Protein p73</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>YAP-Signaling Proteins</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV9v0zAUxSMEYmPwDRDyE28N145jOy9I1djYpCEmWp4tx3FaV4kdbGeofHrctWLwwpOv5HPO_fMrircYSgyYfdiVox-0GUoCwEsQJYB4VpxjaPiCYkafn2rCWX1WvIpxB4BpLZqXxRnmQjSMNefFr2_L1eoaL9HVYLVNES0nPyUfbURpG_y82SLl0JfVmqB7lbY_1R59ssHoZN0G3QevHuXJarQOykUd7JSsd6jdZ79BE6_Qeh59QKt5moKJMZfZlox1r4sXvRqieXN6L4rv11fry5vF3dfPt5fLu4WmlIgFrzADAxXtW1XVogZRAakZNwTzvlG0q3FFAUAbIoAzxYhoad9j3JIO466uLoqPx9xpbkfTaeNSUIOcgh1V2EuvrPz3x9mt3PgHSQTBTPAc8P4UEPyP2cQkRxvz5QfljJ-jZHmihuGDkB6FOvgYg-n_NMEgD9DkTh6hyQM0CUJmaNn27u8Bn0wnSk8bmHymB2uCjNoap033iEJ23v6_w2_27KtW</recordid><startdate>20070921</startdate><enddate>20070921</enddate><creator>Matallanas, David</creator><creator>Romano, David</creator><creator>Yee, Karen</creator><creator>Meissl, Katrin</creator><creator>Kucerova, Lucia</creator><creator>Piazzolla, Daniela</creator><creator>Baccarini, Manuela</creator><creator>Vass, J. Keith</creator><creator>Kolch, Walter</creator><creator>O'Neill, Eric</creator><general>Elsevier Inc</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070921</creationdate><title>RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein</title><author>Matallanas, David ; Romano, David ; Yee, Karen ; Meissl, Katrin ; Kucerova, Lucia ; Piazzolla, Daniela ; Baccarini, Manuela ; Vass, J. Keith ; Kolch, Walter ; O'Neill, Eric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4428-73160e034fba358508302567e217f9a4d5134000ce28076a628b4ff11b2d11d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins - genetics</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Nucleus - metabolism</topic><topic>CELLCYCLE</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Humans</topic><topic>Models, Biological</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Protein Transport</topic><topic>Proto-Oncogene Mas</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-raf - metabolism</topic><topic>Serine-Threonine Kinase 3</topic><topic>Signal Transduction</topic><topic>SIGNALING</topic><topic>Transcription Factors</topic><topic>Transcription, Genetic</topic><topic>Tumor Protein p73</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>YAP-Signaling Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matallanas, David</creatorcontrib><creatorcontrib>Romano, David</creatorcontrib><creatorcontrib>Yee, Karen</creatorcontrib><creatorcontrib>Meissl, Katrin</creatorcontrib><creatorcontrib>Kucerova, Lucia</creatorcontrib><creatorcontrib>Piazzolla, Daniela</creatorcontrib><creatorcontrib>Baccarini, Manuela</creatorcontrib><creatorcontrib>Vass, J. Keith</creatorcontrib><creatorcontrib>Kolch, Walter</creatorcontrib><creatorcontrib>O'Neill, Eric</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matallanas, David</au><au>Romano, David</au><au>Yee, Karen</au><au>Meissl, Katrin</au><au>Kucerova, Lucia</au><au>Piazzolla, Daniela</au><au>Baccarini, Manuela</au><au>Vass, J. Keith</au><au>Kolch, Walter</au><au>O'Neill, Eric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2007-09-21</date><risdate>2007</risdate><volume>27</volume><issue>6</issue><spage>962</spage><epage>975</epage><pages>962-975</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene
puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17889669</pmid><doi>10.1016/j.molcel.2007.08.008</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - metabolism Apoptosis Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Cell Line, Tumor Cell Nucleus - metabolism CELLCYCLE DNA-Binding Proteins - metabolism Humans Models, Biological Nuclear Proteins - metabolism Phosphoproteins - metabolism Phosphorylation Protein Binding Protein Serine-Threonine Kinases - metabolism Protein Transport Proto-Oncogene Mas Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-raf - metabolism Serine-Threonine Kinase 3 Signal Transduction SIGNALING Transcription Factors Transcription, Genetic Tumor Protein p73 Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism YAP-Signaling Proteins |
| title | RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein |
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