A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death
AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide dismutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF...
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| Veröffentlicht in: | The Journal of biological chemistry 2005-02, Vol.280 (6), p.4532-4543 |
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| creator | Kanekura, Kohsuke Hashimoto, Yuichi Kita, Yoshiko Sasabe, Jumpei Aiso, Sadakazu Nishimoto, Ikuo Matsuoka, Masaaki |
| description | AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide dismutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overexpression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity. |
| doi_str_mv | 10.1074/jbc.M410508200 |
| format | Article |
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We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overexpression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M410508200</identifier><identifier>PMID: 15579468</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Androstadienes - pharmacology ; Animals ; Apoptosis ; Cell Death ; Cell Line ; Cells, Cultured ; CHO Cells ; Cricetinae ; DNA - metabolism ; Down-Regulation ; Enzyme Inhibitors - pharmacology ; Escherichia coli - metabolism ; Glutathione - chemistry ; Glutathione Transferase - metabolism ; GTP Phosphohydrolases - metabolism ; Guanine - chemistry ; Guanine Nucleotide Exchange Factors - metabolism ; Humans ; Immunoblotting ; Mice ; Models, Biological ; Motor Neurons - metabolism ; Mutation ; Neurons - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Plasmids - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; rac1 GTP-Binding Protein - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Small Interfering - metabolism ; Sepharose - chemistry ; Superoxide Dismutase - genetics ; Time Factors ; Transfection ; Wortmannin</subject><ispartof>The Journal of biological chemistry, 2005-02, Vol.280 (6), p.4532-4543</ispartof><rights>2005 © 2005 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c551t-129ceb49a8387b0e7906f6b5d646db886eb5db43e57b4b69d746b5fb076cf1323</citedby><cites>FETCH-LOGICAL-c551t-129ceb49a8387b0e7906f6b5d646db886eb5db43e57b4b69d746b5fb076cf1323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15579468$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanekura, Kohsuke</creatorcontrib><creatorcontrib>Hashimoto, Yuichi</creatorcontrib><creatorcontrib>Kita, Yoshiko</creatorcontrib><creatorcontrib>Sasabe, Jumpei</creatorcontrib><creatorcontrib>Aiso, Sadakazu</creatorcontrib><creatorcontrib>Nishimoto, Ikuo</creatorcontrib><creatorcontrib>Matsuoka, Masaaki</creatorcontrib><title>A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide dismutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. 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Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.</description><subject>Androstadienes - pharmacology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell Death</subject><subject>Cell Line</subject><subject>Cells, Cultured</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>DNA - metabolism</subject><subject>Down-Regulation</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Escherichia coli - metabolism</subject><subject>Glutathione - chemistry</subject><subject>Glutathione Transferase - metabolism</subject><subject>GTP Phosphohydrolases - metabolism</subject><subject>Guanine - chemistry</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Motor Neurons - metabolism</subject><subject>Mutation</subject><subject>Neurons - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Plasmids - metabolism</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Sepharose - chemistry</subject><subject>Superoxide Dismutase - genetics</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Wortmannin</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kV9v0zAUxSMEYmXwyiOyeJhAalo7f5zkMWrZmNZqFRsS4sWynZvGI7WD7TDKR-RT4a2V9oRf7Cv_7rlH90TRW4JnBBfZ_E7I2TojOMdlgvGzaEJwmcZpTr49jyYYJySukrw8iV45d4fDySryMjoheV5UGS0n0d8afeGSzDedcUPHvWr2vdLGKW96lMZXSnMH8_qHT1GtvYr5YAZvvJJow313z_dTdGvVdgsWGiT2qO6d0qvzKfIdoI01zSg9Mu1jWa9uEnQBGqYPWnxrtPoDDi3G-Xcdu3EAa36rBtBSud3ow1z04eZ6ST6idai0j5UOamHM2nijYbRG8x4toO_REoKZ19GLlvcO3hzv0-jr-afbxed4dX1xuahXscxz4mOSVBJEVvEyLQuBoagwbanIG5rRRpQlhfAWWQp5ITJBq6bIwm8rcEFlS9IkPY3ODrqDNT9HcJ7tlJPBBtdgRsdIEZQoLQI4O4DSGucstGywasftnhHMHtJjIT32lF5oeHdUHsUOmif8GFcA3h-ATm27e2WBCWVkBzuWlJhRluWP_soDBGEJvxRY5qQCHTYXGqRnjVH_M_APIKq1Iw</recordid><startdate>20050211</startdate><enddate>20050211</enddate><creator>Kanekura, Kohsuke</creator><creator>Hashimoto, Yuichi</creator><creator>Kita, Yoshiko</creator><creator>Sasabe, Jumpei</creator><creator>Aiso, Sadakazu</creator><creator>Nishimoto, Ikuo</creator><creator>Matsuoka, Masaaki</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>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20050211</creationdate><title>A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death</title><author>Kanekura, Kohsuke ; 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We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overexpression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15579468</pmid><doi>10.1074/jbc.M410508200</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2005-02, Vol.280 (6), p.4532-4543 |
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| subjects | Androstadienes - pharmacology Animals Apoptosis Cell Death Cell Line Cells, Cultured CHO Cells Cricetinae DNA - metabolism Down-Regulation Enzyme Inhibitors - pharmacology Escherichia coli - metabolism Glutathione - chemistry Glutathione Transferase - metabolism GTP Phosphohydrolases - metabolism Guanine - chemistry Guanine Nucleotide Exchange Factors - metabolism Humans Immunoblotting Mice Models, Biological Motor Neurons - metabolism Mutation Neurons - metabolism Phosphatidylinositol 3-Kinases - metabolism Plasmids - metabolism Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt rac1 GTP-Binding Protein - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering - metabolism Sepharose - chemistry Superoxide Dismutase - genetics Time Factors Transfection Wortmannin |
| title | A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death |
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