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  • The EMBO Journal (2005) 24, 2458 - 2471
  • doi:10.1038/sj.emboj.7600708

Published online: 9 June 2005

TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria

Olav Gressner1, Tobias Schilling2, Katja Lorenz1, Elisa Schulze Schleithoff1, Andreas Koch1, Henning Schulze-Bergkamen3, Anna Maria Lena4, Eleonora Candi4, Alessandro Terrinoni4, Maria Valeria Catani4, Moshe Oren5, Gerry Melino6, Peter H Krammer3, Wolfgang Stremmel1 and Martina Müller1

  1. Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
  2. Department of Internal Medicine I, Endocrinology, University Hospital, Heidelberg, Germany
  3. Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
  4. Department of Experimental Medicine, IDI-IRCCS, c/o University of Rome, Tor Vergata, Rome, Italy
  5. Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
  6. Medical Research Council, Toxicology Unit, University of Leicester, Leicester, UK

Correspondence to:

Martina Müller, Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel.: +49 6221 5638795; Fax: +49 6221 564395; E-mail: martina_mueller-schilling@med.uni-heidelberg.de

Received 8 December 2004; Accepted 18 May 2005

TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63. We investigated the downstream mechanisms by which TAp63alpha elicits apoptosis. TAp63alpha directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63alpha can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63alpha and the mitochondrial apoptosis pathway. TAp63alpha upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63alpha is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63alpha in the induction of apoptosis and chemosensitivity.

  • Keywords:

    • apoptosis,
    • CD95,
    • chemosensitivity,
    • TAp63,
    • TRAIL