TAp63α induces apoptosis by activating signaling via death receptors and mitochondria

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 TAp63a elicits apoptosis. TAp63a 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.

MicroRNAs as regulators of death receptors signaling

“…34 Zhang et al demonstrated that miR-21 is also significantly overexpressed in human gastric cancer tissues and cell lines. Forced expression of miR-21 significantly enhanced cell proliferation and invasion in AGS, a human gastric-cancer cell line; conversely, knockdown of miR-21 by inhibitors caused a significant reduction in cell proliferation and a significant increase in apoptosis by targeting RECK, a known tumor suppressor, in gastric cancer.…”

Identification of New p63 Targets in Human Keratinocytes

“…55 Recent profiling experiments with TAp63 identified several pro-apoptotic targets. 16 We find very few such genes in our screening, which employs cells that essentially express DNp63a. Among these, Caspase 10 is repressed.…”

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

“…Second, endogenous TAp73 can be stabilized by DNA-damaging agents and its ablation can result in chemoresistance (Bergamaschi et al, 2003;Irwin et al, 2003;Urist et al, 2004). Although less explored, endogenous TAp63 can also determine chemotherapeutic efficiency (Gressner et al, 2005). Third, Flores et al (2002) showed that p63 and p73 are required by p53 to activate a few proapoptotic genes in mouse embryo fibroblasts (MEFs) expressing adenoviral E1A.…”