p53 Isoforms as Cancer Biomarkers and Therapeutic Targets

Abstract

This review aims to summarize the implications of the major isoforms of the tumor suppressor protein p53 in aggressive cancer development. The current knowledge of p53 isoforms, their involvement in cell-signaling pathways, and their interactions with other cellular proteins or factors suggests the existence of an intricate molecular network that regulates their oncogenic function. Moreover, existing literature about the involvement of the p53 isoforms in various cancers leads to the proposition of therapeutic solutions by altering the cellular levels of the p53 isoforms. This review thus summarizes how the major p53 isoforms Δ40p53α/β/γ, Δ133p53α/β/γ, and Δ160p53α/β/γ might have clinical relevance in the diagnosis and effective treatments of cancer.

Keywords: biomarker; cancer; p53 isoforms; therapeutic target.

Figure 1

Constitution of the human TP53 gene and p53 isoforms. (A) Schematic representation of different elements of the TP53 gene. The TP53 gene is composed of 11 exons marked with numbers 1–11. It has two promoter regions P1 and P2, which produce transcripts of different length for expression of different p53 isoforms. The RNA transcripts for FL53 and its isoforms are also generated by alternative splicing of the introns (i2 and i9), and alternative initiation of translation. The stop codons (T) present in i2 and exon 11 are indicated with T. (B) Schematic representation of the p53 isoforms. p53α (FLp53) has seven structural components: two transactivation domains (TAD-1 and -2), a proline-rich domain (PRD), a DNA binding domain (DBD), a nuclear localization signaling region (NLS), oligomerization domain (OD), and a negative regulation domain (α). Δ40p53, Δ133p53, and Δ160p53 isoforms have a deletion of 40, 133, and 160 amino acids from the N-terminus, respectively. Their start codons are indicated. The β and γ isoforms lack the OD and the α domains in the C-terminus, and instead have extensions DQTSFQKENC and MLLDLRWCYFLINSS, respectively.

Figure 2

Expression of the p53 isoforms is regulated by different mechanisms. (A) Regulation at the levels of transcription and translation. At the transcriptional level, alternative promoter usage (P1 and P2) lead to the production of mRNAs for different p53 isoforms. Moreover, alternative splicing (Λ) of the introns i2 and i9, guided by G-quadruplex structures and serine/arginine-rich (SR) splicing factors (SRSFs), respectively, govern expression of the p53 N- and C- terminal variant isoforms. In addition, two distinct internal ribosome entry sites (IRESs) under action of the IRES-interacting trans-acting factors (ITAFs) can modulate the expression of p53 and Δ40p53 at the level of translation. (B) The degradation mechanisms of p53 and its isoforms. Nonsense-mediated decay (NMD) degrades the p53β and p53γ mRNAs post-transcriptionally. The MDM2-mediated ubiquitination-26S proteasome pathway degrades wild-type p53. Δ40p53 forms a heterotetramer with p53, which prohibits MDM2-mediated degradation. Proteasome-independent degradation pathways, such as the digestive organ expansion factor (Def) protein-mediated pathway and autophagy, can degrade Δ133p53α. STUB1, a chaperone-associated ubiquitin ligase, can protect Δ133p53α from autophagic degradation.

Figure 3

p53 isoforms modulate the p53-mediated cellular activities. Different cellular stresses such as ER stress, cell contact, DNA damage, oncogene expression, and oxidative stress activate the p53 signaling pathway. The TP53 gene produces multiple isoforms: p53α, p53β, p53γ, Δ40p53α/β/γ, Δ133p53α/β/γ, and Δ160p53α/β/γ. Isoforms Δ40p53, Δ133p53, and Δ160p53 have been reported to affect biological activities such as cell cycle arrest, senescence, apoptosis, and DNA DAB repair by inducing (green line) or repressing (red line) p53 target gene expression. Furthermore, p53 isoforms can regulate the expression of p53 target genes either directly (solid red and green line) or indirectly (dash red and green line). 14-3-3σ is a target gene of p53, and it induces cell cycle arrest. p53 can induce senescence by transactivating its target genes p21 and miR-34a. Activating p53 target genes such as Bcl-2 and Bcl-xL inhibits apoptosis, while p53 can induce apoptosis by activating pro-apoptotic proteins such as Bax and PIDD. Activating several p53 target genes such as RAD51, RAD52, and LIG4 contributes to DNA DSB repair.

Figure 4

Mechanisms of Δ133p53-induced tumor development via several signaling pathways, including NF-κB, JAK-STAT, RhoA-ROCK, and IFN. In cancer cells, Δ133p53 expression induces the expression of NF-κB target genes, including IL-6, a key factor for activating phosphorylation of STAT. In addition, type I and II IFNs IFN-α, IFN-β, and IFN-γ can also activate the JAK-STAT signaling. STAT can stimulate the transcription of its target genes including Bcl-xL, Bcl-2, and c-Myc. STAT can also activate NF-κB. The activated NF-κB can also induce the transcription of various target genes, such as IL-6, IL-8, Bcl-xL, Bcl-2, and c-Myc. The RhoA-ROCK signaling pathway can interact with the JAK-STAT signaling pathway, resulting in increased phosphorylation of STAT. These pathways regulate genes involved in several processes, such as pro-inflammation, anti-apoptosis, and cell cycle progression, all of which aid in tumor development.