Adaptive homeostasis and the p53 isoform network

Abstract

All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis. The TP53 gene encodes a network of proteins (p53 isoforms) with similar and distinct biochemical functions. The p53 network carries out multiple biological activities enabling cooperation between individual cells required for long-term survival of multicellular organisms (animals) in response to an ever-changing environment caused by mutation, infection, metabolic alteration or damage. In this review, we suggest that the p53 network has evolved as an adaptive response to pathogen infections and other environmental selection pressures.

Keywords: homeostasis; immune response; inflammation; p53 isoforms; pathogen.

Figure 1. Schematic illustrating the similarities between the processes leading to cancer (Hallmarks of Cancer) and the processes involved in adapting to virus infection

Similar hallmarks between cancer development and the cellular response to viral replication are shown in purple. These include avoiding immune cell death, immune checkpoint inhibition, promoting metabolic reprogramming, avoiding programmed cell death, overriding growth suppressors (TP53) and cell cycle arrest. Hallmarks specific to cancer and viral replication are represented in orange and blue respectively.

Figure 2. Structure of the TP53 gene, encoded transcripts (A) and proteins (B)

(A) Schematic demonstrating the TP53 gene locus and the 9 TP53 RNA transcripts known to be generated by alternative splicing and alternative promoter usage (P1 and P2). At the top of the figure, exons represented by blue boxes, including the regions the alternatively spliced transcripts α, β and γ variants. 5’UTR and 3’UTR are shown in orange. (B) Schematic of the canonical p53 protein and the 12 known isoforms. TAD1 Transactivation domain 1, TAD2 Transactivation domain 2, PrD Proline‐rich domain, NLS nuclear localization signal, OD Oligomerization domain.

Figure 3. Map illustrating regions on p53 protein that are bound by viral proteins post infection

Schematic of the canonical p53 protein and the 12 known isoforms. TAD1 Transactivation domain 1, TAD2 Transactivation domain 2, PrD Proline‐rich domain, NLS nuclear localization signal, OD Oligomerization domain. The horizontal bars at the bottom show the amino acids (aa) bound by viral proteins on p53 and the overlap with potential p53 protein isoforms.

Figure 4. Model illustrating the role of the p53 network in maintaining homeostasis

(A) Schematic showing the role of different p53 isoforms in biological processes and their influence on each other. (B) Cells and organisms are continuously exposed to stimulus from external and internal sources. Under physiological conditions, a balanced p53 network responds to these stimuli and regulates immune response and inflammation to maintain cellular and organismal homeostasis. (C) Prolonged exposure to a variety of external and internal stimuli causes an imbalance in the p53 network, which in turn results in aberrant immune response and chronic inflammation. These changes result in loss of cellular and organismal homeostasis resulting in pathologies associated with chronic diseases.