Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition
Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2...
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| Veröffentlicht in: | Journal of Immunology 2007-05, Vol.178 (9), p.5443-5453 |
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| creator | Mao, Changchuin Tili, Esmerina G Dose, Marei Haks, Marielle C Bear, Susan E Maroulakou, Ioanna Horie, Kyoji Gaitanaris, George A Fidanza, Vincenzo Ludwig, Thomas Wiest, David L Gounari, Fotini Tsichlis, Philip N |
| description | Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing beta-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes. |
| doi_str_mv | 10.4049/jimmunol.178.9.5443 |
| format | Article |
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In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing beta-selection. 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In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing beta-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes.</description><subject>Animals</subject><subject>Cell Proliferation</subject><subject>Cell Survival</subject><subject>Gene Expression</subject><subject>Lymphocyte Activation - genetics</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Isoforms - physiology</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - physiology</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>T-Lymphocytes - immunology</subject><subject>Thymus Gland - cytology</subject><subject>Thymus Gland - immunology</subject><subject>Transgenes</subject><issn>0022-1767</issn><issn>1550-6606</issn><issn>1365-2567</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctOwzAQRS0EoqXwBUgoK1il-BHb8RKVV6UKWLRry0mc1iWJW9uh6t-T0lawYzWjqzN3MQeAawSHCUzE_dLUddvYaoh4OhRDmiTkBPQRpTBmDLJT0IcQ4xhxxnvgwvslhJBBnJyDHuJJggWmfZDPGr1uVRWNbBOcydpgbBPZMnr4DNHY29K62kemicJCR4-2zSodv-m5CuZLR8Eeow_rzU80XWxrm29DtznV7ELbXIKzUlVeXx3mAMyen6aj13jy_jIePUziPEEoxFgVKiMwU1ClRGlKac60yBXlaYlokRYCpYQwRrFgeYE5LlIiUkhRIRilPCMDcLvvXTm7brUPsjY-11WlGm1bLznc8Zj_CyLBGCaQdCDZg7mz3jtdypUztXJbiaDcSZBHCbKTIIXcSeiubg71bVbr4vfm8PUOuNsDCzNfbIzT0teqqjocyc1m86fqGwCZky8</recordid><startdate>20070501</startdate><enddate>20070501</enddate><creator>Mao, Changchuin</creator><creator>Tili, Esmerina G</creator><creator>Dose, Marei</creator><creator>Haks, Marielle C</creator><creator>Bear, Susan E</creator><creator>Maroulakou, Ioanna</creator><creator>Horie, Kyoji</creator><creator>Gaitanaris, George A</creator><creator>Fidanza, Vincenzo</creator><creator>Ludwig, Thomas</creator><creator>Wiest, David L</creator><creator>Gounari, Fotini</creator><creator>Tsichlis, Philip N</creator><general>Am Assoc Immnol</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20070501</creationdate><title>Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition</title><author>Mao, Changchuin ; Tili, Esmerina G ; Dose, Marei ; Haks, Marielle C ; Bear, Susan E ; Maroulakou, Ioanna ; Horie, Kyoji ; Gaitanaris, George A ; Fidanza, Vincenzo ; Ludwig, Thomas ; Wiest, David L ; Gounari, Fotini ; Tsichlis, Philip N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-2adab30ba0a83ae555c6e9ca578f15d8d91833665296cd272d8398051d96557b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Cell Proliferation</topic><topic>Cell Survival</topic><topic>Gene Expression</topic><topic>Lymphocyte Activation - genetics</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein Isoforms - physiology</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - physiology</topic><topic>Receptors, Antigen, T-Cell - immunology</topic><topic>T-Lymphocytes - immunology</topic><topic>Thymus Gland - cytology</topic><topic>Thymus Gland - immunology</topic><topic>Transgenes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mao, Changchuin</creatorcontrib><creatorcontrib>Tili, Esmerina G</creatorcontrib><creatorcontrib>Dose, Marei</creatorcontrib><creatorcontrib>Haks, Marielle C</creatorcontrib><creatorcontrib>Bear, Susan E</creatorcontrib><creatorcontrib>Maroulakou, Ioanna</creatorcontrib><creatorcontrib>Horie, Kyoji</creatorcontrib><creatorcontrib>Gaitanaris, George A</creatorcontrib><creatorcontrib>Fidanza, Vincenzo</creatorcontrib><creatorcontrib>Ludwig, Thomas</creatorcontrib><creatorcontrib>Wiest, David L</creatorcontrib><creatorcontrib>Gounari, Fotini</creatorcontrib><creatorcontrib>Tsichlis, Philip N</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of Immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mao, Changchuin</au><au>Tili, Esmerina G</au><au>Dose, Marei</au><au>Haks, Marielle C</au><au>Bear, Susan E</au><au>Maroulakou, Ioanna</au><au>Horie, Kyoji</au><au>Gaitanaris, George A</au><au>Fidanza, Vincenzo</au><au>Ludwig, Thomas</au><au>Wiest, David L</au><au>Gounari, Fotini</au><au>Tsichlis, Philip N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition</atitle><jtitle>Journal of Immunology</jtitle><addtitle>J Immunol</addtitle><date>2007-05-01</date><risdate>2007</risdate><volume>178</volume><issue>9</issue><spage>5443</spage><epage>5453</epage><pages>5443-5453</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><eissn>1365-2567</eissn><abstract>Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing beta-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>17442925</pmid><doi>10.4049/jimmunol.178.9.5443</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Cell Proliferation Cell Survival Gene Expression Lymphocyte Activation - genetics Mice Mice, Knockout Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Protein Isoforms - genetics Protein Isoforms - metabolism Protein Isoforms - physiology Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-akt - physiology Receptors, Antigen, T-Cell - immunology T-Lymphocytes - immunology Thymus Gland - cytology Thymus Gland - immunology Transgenes |
| title | Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition |
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