| First Author | Biju MP | Year | 2004 |
| Journal | Mol Cell Biol | Volume | 24 |
| Issue | 20 | Pages | 9038-47 |
| PubMed ID | 15456877 | Mgi Jnum | J:93322 |
| Mgi Id | MGI:3056854 | Doi | 10.1128/MCB.24.20.9038-9047.2004 |
| Citation | Biju MP, et al. (2004) Vhlh gene deletion induces hif-1-mediated cell death in thymocytes. Mol Cell Biol 24(20):9038-47 |
| abstractText | The von Hippel-Lindau gene product (pVHL) targets the alpha subunit of basic helix-loop-helix transcription factor hypoxia-inducible factor (HIF) for proteasomal degradation. Inactivation of pVhl in the mouse germ line results in embryonic lethality, indicating that tight control of Hif-mediated adaptive responses to hypoxia is required for normal development and tissue function. In order to investigate the role of pVhl in T-cell development, we generated mice with thymocyte-specific inactivation of Vhlh resulting in constitutive transcriptional activity of Hif-1, as well as mice with thymocyte-specific repression of Hif-1 in a wild-type and Vhlh-deficient background. Thymi from Vhlh-deficient mice were small due to a severe reduction in the total number of CD4/CD8-double-positive thymocytes which was associated with increased apoptosis in vivo and in vitro. Increased apoptosis was a result of enhanced caspase 8 activity, while Bcl-2 and Bcl-X(L) transgene expression had little effect on this phenotype. Inactivation of Hif-1 in Vhlh-deficient thymocytes restored thymic cellularity as well as thymocyte viability in vitro. Our data suggest that tight regulation of Hif-1 via pVhl is required for normal thymocyte development and viability and that an increase in Hif-1 transcriptional activity enhances caspase 8-mediated apoptosis in thymocytes. |
