TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria.
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.
Gressner
Olav
O
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany.
Schilling
Tobias
T
Lorenz
Katja
K
Schulze Schleithoff
Elisa
E
Koch
Andreas
A
Schulze-Bergkamen
Henning
H
Lena
Anna Maria
AM
Candi
Eleonora
E
Terrinoni
Alessandro
A
Catani
Maria Valeria
MV
Oren
Moshe
M
Melino
Gerry
G
Krammer
Peter H
PH
Stremmel
Wolfgang
W
Müller
Martina
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012269:Ribosomal Proteins; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism
C506592:APAF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; C097041:DAP3 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; D012269:Ribosomal Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C069930:rad9 protein; D020169:Caspases