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.

p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

“…The Δ40p53 isoforms (also named N-terminally truncated p53 protein (p53/47), or ΔNp53) are generated by alternative splicing of intron 2 and/or alternative initiation of translation [165]. Since these isoforms lack the first 39 amino acids, they do not have TAD1, but retain TAD2.…”

“…Finally, the Δ160p53α, Δ160p53β, and Δ160p53γ isoforms are characterized by a lack of the first 159 amino acids [165]. Although the currently available information about these p53 variants is very limited, it was found that this group of p53 isoforms was expressed in K562 cells, which were originally considered “p53-null” cells [171,172].…”

“…Although the involvement of p53 in cancer pathogenesis is typically reflected in the presence of numerous mutants (see below), some types of cancer, such as AML or breast cancer, do not have frequent p53 mutations [165]. Based on the observation that different p53 isoforms can be differentially expressed in tumors compared with normal tissue, an importance of alternative isoforms in carcinogenesis became clear [174,175,176].…”

“…Although regardless of TP53 mutation status in cancer cells, abnormal expression of p53 isoforms is known to play an active role in the formation and progression of cancer [165], questions about how often p53 isoforms are affected by cancer-related mutations and how various p53 activities can be modulated by mutating alternative isoforms remain open. However, knowing the detrimental effects of mutations and abnormal expression of p53 isoforms, one can only imagine what damage can be caused by proteoforms generated as a result of the combined action of these two factors.…”

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records

“…Interestingly, a multidisciplinary team at Yale University, led by Yale Cancer Center members, has confirmed that NF1 is a “major player” in the development of skin cancer [47], which is also observed in this study. The TP53 gene responds to diverse cellular stress to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, and/or changes in metabolism [48]. Mutations in TP53 may result in adrenal cortical carcinoma [49], breast cancer [50], choroid plexus papilloma [51], colorectal cancer [52], hepatocellular carcinoma [53], Li-Fraumeni syndrome [54], nasopharyngeal carcinoma [55], osteosarcoma [56], pancreatic cancer [57], basal cell carcinoma [58], and glioma susceptibility [59].…”