The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases

Abstract

p53, first described four decades ago, is now established as a master regulator of cellular stress response, the "guardian of the genome". p53 contributes to biological robustness by behaving in a cellular-context dependent manner, influenced by several factors (e.g., cell type, active signalling pathways, the type, extent and intensity of cellular damage, cell cycle stage, nutrient availability, immune function). The p53 isoforms regulate gene transcription and protein expression in response to the stimuli so that the cell response is precisely tuned to the cell signals and cell context. Twelve isoforms of p53 have been described in humans. In this review, we explore the interactions between p53 isoforms and other proteins contributing to their established cellular functions, which can be both tumour-suppressive and oncogenic in nature. Evidence of p53 isoform in human cancers is largely based on RT-qPCR expression studies, usually investigating a particular type of isoform. Beyond p53 isoform functions in cancer, it is implicated in neurodegeneration, embryological development, progeroid phenotype, inflammatory pathology, infections and tissue regeneration, which are described in this review.

Keywords: cancer; isoforms; p53; p53 response.

Figure 1

(a) p53 mRNAs. The TP53 gene encodes 9 mRNA transcripts. (b) Functional domains of p53 and its isoforms. p53 contains seven functional domains which are the transactivation domain 1 (TAD1), the transactivation domain 2 (TAD2), the proline-rich domain (PRD), the DNA binding domain (DBD), the hinge domain (HD), the oligomerization domain (OD) and the negative regulation domain (α). At its N-terminus, lies an intrinsic disorder region (IDR) consisting of two acidic trans-activation domains (TAD), TAD1 (residues 1−39) and TAD2 (residues 40–61) and a proline-rich domain (PRD) (residues 62–93). This is followed by a DNA-binding domain (DBD) (residues 94–290) and a hinge domain (HD) (residues 291–324). At its carboxyl terminus, p53 comprises an oligomerization domain (OD) (residues 325–356) and a negative regulation domain (α) (residues 357–393).

Figure 2

Schematic overview of p53 isoform interactions mediating transactivation. (a) p53 isoforms can form hetero-oligomers with p53α to mediate transactivation. For example, Δ40p53 α/p53α hetero-oligomers can modulate the transcriptional activity of promoters of IGF1-receptor and Nanog, thus controlling the switch from pluripotency to differentiation [64]. (b) p53 isoforms can transactivate target genes only in the presence of p53α. For example, p53β can indirectly interact with p53α in the presence of the BAX promoter DNA, modulating its promoter activity. Endogenous p53β binds to the BAX promoter in MCF7 cells; however, the exact p53β binding sequence on the BAX promoter remains to be elucidated [16]. (c) p53 isoforms can independently mediate transactivation. Δ40p53α can transactivate BAX and GADD45 in p53-null cells; however, whether Δ40p53α mediates transactivation as an oligomeric complex remains unclear (represented by dotted lines) [24]. (d) p53 isoforms can mediate transactivation via cooperation with other proteins. p73 and Δ133p53α isoforms can cooperate in a p53-null environment to mediate DNA repair [72].

Figure 3

A TP53 mutational event can result in the generation of Mutp53α, WTp53 and Mutp53 isoform. Mutp53α can mediate tumorigenesis via the following mechanisms: loss of WTp53 activity by dominant-negative effect (DNE) over the WTp53 allele. Alternatively, Mutp53α via gain of function (GOF) mutations promote oncogenic effects in a cell context-dependent manner [86]. WTp53 isoforms can contribute to tumour suppressive functions (e.g., Δ133p53α isoforms can coordinate with p73 to mediate DNA repair) and may also possess intrinsic oncogenic functions (e.g., Δ133p53β isoforms mediating angiogenesis). Preliminary evidence also suggests that WTp53 isoforms (Δ160p53α) can contribute to the GOF effects of Mutp53α [87]. The function of Mutp53 isoform in tumorigenesis remains unclear (represented by dotted lines) but, could theoretically mediate both oncogenic and tumour suppressive effects. Together this provides an overview of the possible downstream p53 isoform effects following a TP53 mutational event.