Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting

Abstract

TP53 is the most commonly mutated gene in human cancer with over 100,000 literature citations in PubMed. This is a heavily studied pathway in cancer biology and oncology with a history that dates back to 1979 when p53 was discovered. The p53 pathway is a complex cellular stress response network with multiple diverse inputs and downstream outputs relevant to its role as a tumor suppressor pathway. While inroads have been made in understanding the biology and signaling in the p53 pathway, the p53 family, transcriptional readouts, and effects of an array of mutants, the pathway remains challenging in the realm of clinical translation. While the role of mutant p53 as a prognostic factor is recognized, the therapeutic modulation of its wild-type or mutant activities remain a work-in-progress. This review covers current knowledge about the biology, signaling mechanisms in the p53 pathway and summarizes advances in therapeutic development.

Keywords: Apoptosis; CDKN1A; Cancer; Cell cycle; DR5; Puma; Therapeutics; miRNA; p53.

Figure 1.. Overview of p53 activation, regulation, and transcriptional cellular response output.

Cellular stresses including DNA damage, oncogene activation, hypoxia, and replication/translation stress activate sensor proteins ATM, ATR, Chk1, Chk2, DNA-PK, and p14ARF. These kinases phosphorylate p53 leading to its stabilization, oligomerization, and binding to the p53RE. P53 stability is mainly regulated by MDM2, which is also a p53-target thus forming a negative feedback loop. Further protein modifiers and cofactors that bind to the p53 protein regulate the transcriptional activity of its target genes. This multi-step process of p53 activation ultimately regulates the stress input to the appropriate biological response outcome. Created with BioRender.com

Figure 2.. Opposing effects of wild-type and mutant p53 regulation in cancer biology.

Wild-type and mutant p53 respond to a variety of cellular stresses (DNA damage, hypoxia, metabolic stress, and oxidative stress). Their regulation occurs at the transcriptional, post-transcriptional, and post-translational level. At the transcriptional level, wild-type p53 binds directly at p53 response elements (RE) whereas mutant p53 binds to other transcription factors (TF), example Y to regulate a gene X, as indicated. Both wild-type and mutant p53 can regulate the expression of microRNAs and interact directly/indirectly with other proteins to induce a cellular response. Wild-type p53 biological response is tumor suppression, unlike mutant p53 where its response leads to metastasis and therapy resistance. Green color: positively regulated, red color negative regulated. Created with BioRender.com

Figure 3.. Current p53 therapeutic strategies.

Several approaches have been taken to target one of the most commonly mutated genes in tumors, p53. Unfortunately, none of the identified drugs are approved by the FDA. Thus, the current work aims to address the unmet need of small molecules that restore the p53-pathway and its functional signaling in tumor suppression.