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TAp63α induces apoptosis by activating signaling via death receptors and mitochondria
Open accessAbstract
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.
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“TAp63 is a homologue of p53 and is known to mediate both cell cycle arrest and apoptosis (19,38).”
From MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells (2008) · cites this paper as [38]
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Metadata
- Authors
- Gressner, O., Schilling, T., Lorenz, K., Schulze Schleithoff, E., Koch, A., Schulze‐Bergkamen, H., Maria Lena, A., Candi, E., Terrinoni, A., Valeria Catani, M., Oren, M., Melino, G., Krammer, P. H., Stremmel, W., & Müller, M.
- Affiliations
- University Hospital Heidelberg (DE)
- German Cancer Research Center (DE)
- University of Rome Tor Vergata (IT)
- Weizmann Institute of Science (IL)
- University of Leicester (GB)
- Corresponding author
- Müller, Martina
- ORCID
- Venue
- The EMBO Journal
- Published
- 2005-06-09
- Volume
- 24
- Issue
- 13
- Pages
- 2458-2471
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1173149
- OpenAlex
- W2167669999
- Cited by
- 255
- References
- 52
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 15 · 2017: 8 · 2016: 9 · 2015: 15 · 2014: 13 · 2013: 18 · 2012: 15
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Ministero dell’Istruzione, dell’Università e della Ricerca (QLK3-CT-2002-01956)
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- TAp63α, p63, apoptosis, death receptors, Fas, TNF receptor, TRAIL receptors, mitochondrial apoptosis, Bax, BCL2L11, p53 binding sites, chemosensitivity, chemoresistance, transcriptional activation, epithelial development
- MeSH terms
- Bcl-2-Like Protein 11, Antineoplastic Agents, DNA-Binding Proteins, Enzyme Activation, Humans, Membrane Proteins, Mitochondria, Phosphoproteins, Proteins, Proto-Oncogene Proteins, Ribosomal Proteins, Transcription Factors, Signal Transduction, Transcriptional Activation, Trans-Activators, Up-Regulation, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, RNA-Binding Proteins, Apoptosis, Receptors, Tumor Necrosis Factor, Cell Cycle Proteins, Drug Resistance, Neoplasm, fas Receptor, Proto-Oncogene Proteins c-bcl-2, Caspases, Oligonucleotide Array Sequence Analysis, Tumor Suppressor Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Apoptotic Protease-Activating Factor 1
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