PMID:15456877

Citation	Biju, MP, Neumann, AK, Bensinger, SJ, Johnson, RS, Turka, LA and Haase, VH (2004) Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol. Cell. Biol. 24:9038-47
Abstract	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-XL 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.
Links	PubMed PMC517905 Online version:10.1128/MCB.24.20.9038-9047.2004
Keywords	Animals; Apoptosis/physiology; Caspase 8; Caspases/metabolism; Cell Survival; DNA-Binding Proteins/metabolism; Gene Deletion; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; In Situ Nick-End Labeling; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Nuclear Proteins/metabolism; Thymus Gland/cytology; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Von Hippel-Lindau Tumor Suppressor Protein; von Hippel-Lindau Disease/genetics; von Hippel-Lindau Disease/metabolism
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