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TAp63α induces apoptosis by activating signaling via death receptors and mitochondria
Author(s) -
Gressner Olav,
Schilling Tobias,
Lorenz Katja,
Schulze Schleithoff Elisa,
Koch Andreas,
SchulzeBergkamen Henning,
Maria Lena Anna,
Candi Eleonora,
Terrii Alessandro,
Valeria Catani Maria,
Oren Moshe,
Melino Gerry,
Krammer Peter H,
Stremmel Wolfgang,
Müller Martina
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600708
Subject(s) - hepatology , schulze method , medicine , university hospital , general surgery , philosophy , epistemology
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 ΔNp63. We investigated the downstream mechanisms by which TAp63α elicits apoptosis. TAp63α 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 TAp63α can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63α and the mitochondrial apoptosis pathway. TAp63α 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 TAp63α 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 TAp63α in the induction of apoptosis and chemosensitivity.