Uncovering the role of p53 splice variants in human malignancy: a clinical perspective

Abstract

Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets.

Keywords: alternative splicing; cancer; isoforms; p53; p63; p73.

Figure 1

The p53 pathway. Different cellular stresses induce the activation of the upstream mediators (eg, ATM, Chk2, p19ARF), which upregulate p53 by inhibiting p53 interaction with MDM2, its main ubiquitin ligase. Then, p53 activated by mediators activates or represses its target genes according to the final outcome expected. In the absence of stress, p53 regulates many other physiological functions. Abbreviations: DNA, deoxyribonucleic acid; ATM, ataxia telangiectasia mutated; JNK, c-Jun N-terminal kinase; HIPK2, homeodomaininteracting protein kinase 2; HIF-la, hypoxia-inducible factor-la; MDM2, mouse double minute 2; PCAF, p300/CBP-associated factor; GADD45, growth arrest and DNA damage; TRAIL-R2, TNF-related apoptosis-inducing ligand-receptor2.

Figure 2

Many ways to inactivate the p53 pathway in cancer. The p53 pathway can be inactivated directly by mutation, deletion, or methylation of TP53, or indirectly by mutation (*) of mediators of the p53 pathway, proteins encoded by viruses, or a nuclear exclusion of p53. Abbreviations: ATM, ataxia telangiectasia mutated; MDM2, mouse double minute 2; PTEN, phosphatase and tensin homolog.

Figure 3

(A and B) The TP53 gene encodes twelve different isoform proteins. (A) The human TP53 gene structure. The TP53 gene comprises eleven exons and encodes several p53 isoforms using alternative promoters (↱), splicing sites (^), or translational initiation sites (1). (B) Human p53 isoforms. The canonical p53 (p53α) has two transactivation domains (TAD1 aa 1–42 and TAD2 aa 43–63), a proline-rich domain (PXXP aa 64–92), a DNA-binding domain (DBD aa 102–306), a nuclear localization domain (NLS aa 316–325), an oligomerization domain (OD aa 307–355), and a negative-regulation domain (Neg aa 364–393). Abbreviations: MW, molecular weight; kD, kilo Dalton.

Figure 4

p53 isoforms in cancer and targeted therapy. Depending on the cell context, some p53 isoforms, such as Δ133p53α, inhibit the antitumor role of the canonical p53α, while others potentiate its activity. In cancer, the imbalance between the p53 isoforms can promote a prosurvival effect, and thus allows cancer cells to survive. The prosurvival phenotype of these cells can be changed toward the proapoptotic phenotype by altering the p53 isoform-expression profile. Using small molecules targeting the alternative splicing of p53, protein degradation, or p53 internal promoter activity, it could be possible to decrease expression of antiapoptotic isoforms, or on the contrary to increase proapoptotic isoform expression. Abbreviations: IRES, internal ribosome entry site.