| Title | Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia |
| Authors | Ouyang, Kunfu Gomez-Amaro, Rafael Leandro Stachura, David L. Tang, Huayuan Peng, Xiaohong Fang, Xi Traver, David Evans, Sylvia M. Chen, Ju |
| Affiliation | Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. Peking Univ, Shenzhen Grad Sch, Key Lab Chem Genom, Ctr Drug Discovery, Shenzhen 518055, Peoples R China. Univ Calif San Diego, Skaggs Sch Pharm, La Jolla, CA 92093 USA. Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. |
| Keywords | T-CELL DEVELOPMENT INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS PROTEIN-KINASE-C NF-KAPPA-B ALPHA-BETA MOLECULAR PATHOGENESIS LYMPHOCYTE DEVELOPMENT IMMATURE THYMOCYTES NEGATIVE SELECTION NOTCH1 MUTATIONS |
| Issue Date | 2014 |
| Publisher | nature communications |
| Citation | NATURE COMMUNICATIONS.2014,5. |
| Abstract | Calcium ions (Ca2+) function as universal second messengers in eukaryotic cells, including immune cells. Ca2+ is crucial for peripheral T-lymphocyte activation and effector functions, and influences thymocyte selection and motility in the developing thymus. However, the role of Ca2+ signalling in early T-lymphocyte development is not well understood. Here we show that the inositol triphosphate receptors (IP(3)Rs) Ca2+ ion channels are required for proliferation, survival and developmental progression of T-lymphocyte precursors. Our studies indicate that signalling via IP(3)Rs represses Sox13, an antagonist of the developmentally important transcription factor Tcf-1. In the absence of IP3R-mediated Ca2+ signalling, repression of key Notch transcriptional targets-including Hes1-fail to occur in post beta-selection thymocytes, and mice develop aggressive T-cell malignancies that resemble human T-cell acute lymphoblastic leukemia (T-ALL). These data indicate that IP3R-mediated Ca2+ signalling reinforces Tcf-1 activity to both ensure normal development and prevent thymocyte neoplasia. |
| URI | http://hdl.handle.net/20.500.11897/342223 |
| ISSN | 2041-1723 |
| DOI | 10.1038/ncomms5814 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 深圳研究生院待认领 |
