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Molecular and Cellular Biology, October 2004, p. 9038-9047, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.9038-9047.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Vhlh Gene Deletion Induces Hif-1-Mediated Cell Death in Thymocytes{dagger}

Mangatt P. Biju,1,{ddagger} Aaron K. Neumann,1,2,{ddagger} Steven J. Bensinger,1,2 Randall S. Johnson,3 Laurence A. Turka,1,2 and Volker H. Haase1,4*

Department of Medicine,1 Immunology Graduate Group,2 Cell and Molecular Biology Graduate Group, Program in Cell Growth and Cancer, University of Pennsylvania, Philadelphia, Pennsylvania,4 Molecular Biology Section, Division of Biology, University of California San Diego, La Jolla, California3

Received 17 December 2003/ Returned for modification 27 February 2004/ Accepted 19 July 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.

* Corresponding author. Mailing address: Department of Medicine, 700 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104-6144. Phone: (215) 573-1830. Fax: (215) 898-0189. E-mail: vhaase{at}mail.med.upenn.edu.

{ddagger} M.P.B. and A.K.N. contributed equally to this work.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2004, p. 9038-9047, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.9038-9047.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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