1. ¹Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
2. ²Department of Medical Biology, The University of Melbourne, Melbourne, Australia
3. ³Division for Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria

Correspondence: A Strasser, Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Tel: +0061 3 9345 2624; Fax: +0061 3 9347 0852; E-mail: strasser@wehi.edu.au

⁴These two authors share senior authorship.

Received 6 October 2006; Revised 26 November 2007; Accepted 4 January 2008; Published online 8 February 2008.

Abstract

The ability of p53 to induce apoptosis in cells with damaged DNA is thought to contribute greatly to its tumour suppressor function. P53 has been proposed to induce apoptosis via numerous transcriptional targets or even by direct cytoplasmic action. Two transcriptional targets shown to mediate its apoptotic role in several cell types encode Noxa and Puma, BH3-only members of the Bcl-2 family. To test if their functions in p53-dependent apoptosis overlap, we generated mice lacking both. These mice develop normally and no tumours have yet arisen. In embryonic fibroblasts, the absence of both Noxa and Puma prevented induction of apoptosis by etoposide. Moreover, following whole body -irradiation, the loss of both proteins protected thymocytes better than loss of Puma alone. Indeed, their combined deficiency protected thymocytes as strongly as loss of p53 itself. These results indicate that, at least in fibroblasts and thymocytes, p53-induced apoptosis proceeds principally via Noxa and Puma, with Puma having the predominant role in diverse cell types. The absence of tumours in the mice suggests that tumour suppression by p53 requires functions in addition to induction of apoptosis.