TAp63 alpha induces apoptosis by activating signaling via death receptors and mitochondria

O Gressner; T Schilling; K Lorenz; ES Schleithoff; A Koch; H Schulze-Bergkamen; AM Lena; E Candi; A Terrinoni; MV Catani; Moshe Oren; G Melino; PH Krammer; W Stremmel; M Muller

doi:10.1038/sj.emboj.7600708

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TAp63 alpha induces apoptosis by activating signaling via death receptors and mitochondria

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TAp63 alpha induces apoptosis by activating signaling via death receptors and mitochondria

O Gressner, T Schilling, K Lorenz, ES Schleithoff, A Koch, H Schulze-Bergkamen, AM Lena, E Candi, A Terrinoni, MV Catani, …

EMBO Journal, Vol.24(13), pp.2458-2471

Jul/2005

DOI: https://doi.org/10.1038/sj.emboj.7600708

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Abstract

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 DNp63. We investigated the downstream mechanisms by which TAp63 alpha elicits apoptosis. TAp63 alpha 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 TAp63a can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63a and the mitochondrial apoptosis pathway. TAp63a 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 TAp63a 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 TAp63a in the induction of apoptosis and chemosensitivity.

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Title: TAp63 alpha induces apoptosis by activating signaling via death receptors and mitochondria
Creators: O Gressner (null)
T Schilling (null)
K Lorenz (null)
ES Schleithoff (null)
A Koch (null)
H Schulze-Bergkamen (null)
AM Lena (null)
E Candi (null)
A Terrinoni (null)
MV Catani (null)
Moshe Oren (null) - 972WIS_INST___122
G Melino (null)
PH Krammer (null)
W Stremmel (null)
M Muller (null)
Resource Type: Journal article
Publication Details: EMBO Journal, Vol.24(13), pp.2458-2471; Jul/2005
Number of pages: 14
Language: English
DOI: https://doi.org/10.1038/sj.emboj.7600708
Record Identifier: 993266719903596

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