The Δ133p53 Isoforms, Tuners of the p53 Pathway

Abstract

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.

Keywords: aging; cancer; p53; p53 isoforms; Δ133p53.

Figure 1

Representation of canonical p53 (p53α) and the three Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ). p53α contains two transactivation domains (TAD1 and TAD2), the proline-rich domain (PRD), the DNA binding domain (DBD), the hinge domain (HD), the oligomerization domain (OD) and the α-domain. Part of the OD and the α-domain can be alternatively spliced to create the β and γ isoforms. The Δ133p53 isoforms lack TA-1, TA-2, PRD and part of the DBD. The DBD contains 4 highly conserved regions (striped boxes) spanning amino-acids 117–142, 171–181, 234–258 and 270–286 respectively, and the Δ133p53 isoforms lack, therefore, the majority of the first conserved region. Three nuclear localization sequences (NLS) are in the C-terminal part (red dotted lines), one in the HD and two in the α-domain, so the β and γ isoforms only have the first one.

Figure 2

Δ133p53 isoforms through evolution. (A) Alignment of human p53 sequence (accession number NP_001119584) between amino-acid 118 and 167 with the corresponding sequence in African clawed frog (CAA54672), Zebrafish (NP_571402), Chinese hamster (AAC53040), Mouse (BAA82344), Rat (NP_112251), African elephant (XP_010594888.1), dog (BAA78379), Beluga whale (AAL83290), Sheep (CAA57349), Water buffalo (AEG21062), Cattle (CAA57348), Aurochs (BAA08629), Green monkey (XP_008008385), Crab eating macaque (AAB91535), Japanese macaque (AAN64028) and Rhesus macaque (XP_005582844). The phylogenetic tree on the left is a neighbor joining tree without distance correction. The phylogenetic tree and the alignment were designed using Clustal Omega multiple sequence alignment online tool (https://www.ebi.ac.uk/Tools/msa/). (B) To scale representation of N-terminally truncated isoforms in human, zebrafish and drosophila as compared to their respective full-length proteins. Proteins are divided in 3 functional domains: transactivation domain (TAD) in orange, DNA binding domain (DBD) in green and C-terminal domain (CTD) in red. Of note, the identical colors in three species highlight the common functional domains with varying degrees of sequence homology.

Figure 3

Proposed model for the functions of the three Δ133p53 isoforms. Under physiological conditions, Δ133p53α prevents replicative senescence while ensuring genomic integrity of the replicative normal cells. By reducing the number of senescent cells, it reduces senescence-associated secretory phenotype (SASP) secretion which prevents the development of cancer prone microenvironment. Δ133p53α also maintains the astrocytes in a replicative, neuroprotective state which prevents neurodegeneration. Furthermore, Δ133p53α protects CD8+ T-cells from T-cell exhaustion and senescence thereby facilitating cellular immunity against infectious diseases and cancer. Lastly, Δ133p53α isoforms may ensure the maintenance of pluripotent stem cell reserves which is critical for cell renewal in tissues. Taken together, all these activities of Δ133p53α under physiological conditions contribute to normal tissue homeostasis and functions. In the context of cancer, Δ133p53 isoforms may promote tumor progression and aggressiveness. By promoting DNA repair, Δ133p53α isoform may counteract the effect of genotoxic drugs leading to treatment resistance. All three Δ133p53 isoforms promote cancer cell invasion and metastasis by favoring either angiogenesis, vascular smooth muscle cell proliferation and/or epithelial to mesenchymal transition. Furthermore, Δ133p53β promotes cancer stemness phenotype, immunosuppressive microenvironment and chronic inflammation, while Δ133p53α may prevent cancer cells to enter senescence, thus favoring malignant progression.