Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes.

Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA, Haase VH
Mol Cell Biol. 2004 24 (20): 9038-47

PMID: 15456877 · PMCID: PMC517905 · DOI:10.1128/MCB.24.20.9038-9047.2004

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.

MeSH Terms (24)

Animals Apoptosis Caspase 8 Caspases Cell Survival DNA-Binding Proteins 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 Thymus Gland Transcription, Genetic Transcription Factors Tumor Suppressor Proteins Ubiquitin-Protein Ligases von Hippel-Lindau Disease Von Hippel-Lindau Tumor Suppressor Protein

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