HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCRβ-selected mouse thymocytes
| Autor: | Gladys W. Wong, Juan Carlos Zúñiga-Pflücker, Adolfo A. Ferrando, Tak W. Mak, Gisele Knowles |
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| Rok vydání: | 2012 |
| Předmět: |
Receptors
CXCR4 Cell cycle checkpoint Transcription Genetic Cell Survival Cellular differentiation Receptors Antigen T-Cell alpha-beta Immunology Notch signaling pathway Biochemistry Interleukin-7 Receptor alpha Subunit Proto-Oncogene Proteins c-myc Mice Basic Helix-Loop-Helix Transcription Factors Tensin PTEN Animals Cell Lineage HES1 RNA Small Interfering PI3K/AKT/mTOR pathway Cell Proliferation Homeodomain Proteins Thymocytes biology Receptors Notch PTEN Phosphohydrolase Cell Differentiation Cell Biology Hematology Up-Regulation Gene Knockdown Techniques biology.protein Cancer research Transcription Factor HES-1 Signal transduction Gene Deletion Signal Transduction |
| Zdroj: | Blood. 120(7) |
| ISSN: | 1528-0020 |
| Popis: | The developmental progression of immature thymocytes requires cooperative input from several pathways, with Notch signals playing an indispensable role at the T-cell receptor (TCR)–β selection checkpoint. Notch signals affect the activation of the PI3K/Akt pathway, which is required for pTα/TCRβ (pre-TCR)–induced survival, differentiation, and proliferation of developing αβ-lineage thymocytes. However, the molecular players responsible for the interaction between the Notch and PI3K pathways at this critical developmental stage are unknown. Here, we show that Notch induction of Hes1 is necessary to repress the PI3K/Akt pathway inhibitor, PTEN (phosphatase and tensin homolog), which in turn facilitates pre-TCR–induced differentiation. In support of this mechanism, deletion or down-regulation of Pten overcomes the Notch signaling requirement for survival and differentiation during β-selection. In addition, c-Myc is a critical target of Notch at this stage, as c-Myc expression overcomes the Notch signaling requirement for proliferation during β-selection. Collectively, our results point to HES1, via repression of PTEN, and c-Myc as critical mediators of Notch function at the β-selection checkpoint. |
| Databáze: | OpenAIRE |
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