p53 isoforms gain functions

Abstract

Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis. One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response. It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions. The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest. On the other hand, p53 itself induces G1 arrest and has no effect on the G2. The two isoforms D133p53, which lacks the first 133 amino acids, and p53b, which carries an alternative C-terminus, are derived from alternative promoter usage or splicing, respectively, and are together implied in controlling cellular senescence. Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses. This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains.

p53 and Translation Attenuation Regulate Distinct Cell Cycle Checkpoints during Endoplasmic Reticulum (ER) Stress

“…4C). Although p53/47 is able to homooligomerize and hetero-oligomerize with full-length p53, it lacks interaction with mdm2, perhaps explaining the increased stability we observed during ER stress (44). Of note, we were unable to detect the generation of p53/47 in the p53ϩ/ϩ cells despite a report that ER stress leads to the preferential translation of this isoform (23).…”

Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A

“…Total RNA was extracted with RNeasy Mini Kit (Qiagen) following manufacturer's instructions. cDNA synthesis was carried out using the Moloney murine leukaemia virus reverse transcriptase and Oligo(dT) [12][13][14][15][16][17][18] Primer (Invitrogen). RT-qPCR was performed on StepOne real-time PCR system (Applied Biosystems) using TaqMan Gene Expression Master Mix and Assays for p21, 14-3-3s and actin (Applied Biosystems).…”

“…However, it is yet relatively unknown how the activity of p53 downstream factors is synchronized to ensure that the cellular response matches the inflicting damage. The p53 gene encodes various p53 isoforms, each with its own unique activity that help to diversify p53 function in response to different signalling pathways [11][12][13][14][15] . The p53/47 isoform, later called DNp53 or D40p53, lacks the first 40 amino acids of the full-length p53 (p53 FL) and has different activity and stability [16][17][18][19] .…”

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

“…How p53 can react specifically to the different stresses is unclear. Emerging findings suggest that p53 activity on specific targets is regulated by specific p53 isoforms, in the context of specific activating-signals [91]. The structure of the human p53 gene is very complex, alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N-and C-termini which are differentially expressed in normal and cancer cells.…”