A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression

Abstract

p73 is the older sibling of p53 and mimics most of its tumor-suppressor functions. Through alternative promoter usage and splicing, the TP73 gene generates more than two dozen isoforms of which N-terminal truncated DNp73 variants have a decisive role in cancer pathogenesis as they outweigh the positive effects of full-length TAp73 and p53 in acting as a barrier to tumor development. Beyond the prevailing view that DNp73 predominantly counteract cell cycle arrest and apoptosis, latest progress indicates that these isoforms acquire novel functions in epithelial-to-mesenchymal transition, metastasis and therapy resistance. New insight into the mechanisms underlying this behavior reinforced the expectation that DNp73 variants contribute to aggressive cellular traits through both loss of wild-type tumor-suppressor activity and gain-of-function, suggesting an equally important role in cancer progression as mutant p53. In this review, we describe the novel properties of DNp73 in the invasion metastasis cascade and outline the comprehensive p73 regulatome with an emphasis on molecular processes putting TAp73 out of action in advanced tumors. These intriguing insights provoke a new understanding of the acquisition of aggressive traits by cancer cells and may help to set novel therapies for a broad range of metastatic tumors.

p73 and IGF1R Regulate Emergence of Aggressive Cancer Stem–like Features via miR-885-5p Control

“…DNp73 thereby counteracts tumor-suppressive properties of wild-type p53/TAp73 through forming inactive heteromeric complexes with them or by occupying p53-responsive elements on gene promoters. High-expression levels of DNp73 are observed especially in late-stage tumors and metastases, where they significantly correlate with poor patient outcome (1). Numerous studies have provided substantial evidence that DNp73 bestows chemoresistance by decreasing intracellular drug accumulation through upregulation of the ABC transporters A2, A5, and B1 (2,3).…”

p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity

“…The p73 protein has been shown to participate in a wide variety of cellular events, including cell death, self-renewal and cell cycle regulation (Di et al, 2013; Engelmann et al, 2015; Fatt et al, 2014; Killick et al, 2011). The p73 protein has several isoforms characterized by alternative transcription at the N-terminus and alternative splicing at the C-terminus.…”

“…Besides playing an important role in regulating differentiation, cell death, and neural stem cells, p73 is also implicated in neurodegenerative diseases such as Alzheimer's disease (Engelmann et al, 2015; Killick et al, 2011; Yang et al, 2002). The p73 gene has 15 exons and two different transcription start sites.…”

TAp73 transcriptionally represses BNIP3 expression

“…Cells were grown in humidified incubator, at 37 C, in atmosphere of 5% CO 2 RNA extraction and quantitative PCR RNA was extracted from cells by means of RNEasy Mini Kit (Qiagen), according to the Qiagen company protocol. The RNA obtained was quantified by spectrophotometric analysis, and 1 ug of total RNA was used to prepare cDNA with RevertAid H minus First Strand cDNA Synthesis kit (ThermoScientific), using Random primers and protocol from the kit.…”