Abstract
The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, Δ40p53, p53ΔN40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.
Highlights
These data point towards different and specific activities of p47 that rely on its transactivation II (TAII) domain, which would promote particular responses of p53-regulated genes depending on the cellular context
Sensors, the mechanisms involved and the role of p47 are scarcely known, and require closer attention [124,125]. They still emphasize the importance to develop therapeutic strategies aiming to restore the normal activity of p53 in cancer cells and/or to remove the gain of function (GOF) properties linked to mutp53, activating the Endoplasmic reticulum (ER) stress-dependent death pathways
Most studies have focused on the full-length protein without addressing the role of the ER stress-induced isoform p47
Summary
The p53 tumor suppressor is mainly known as a transcription factor that both positively and negatively regulates the expression of a diverse multitude of genes following different insults, such as DNA damage, nutrient deprivation, viral infection, and oncogene activation, among others [1]. Induction of MDM2 and the ATM-mediated phosphorylation of MDM2 and MDMX, constitute a positive regulatory loop towards p53 activation that includes an increase in its half-life and in the rate of p53 protein synthesis [27,28] The latter depends on MDM2 and MDMX’s capacity to bind p53’s mRNA through their C-terminal RING domains [27,28,29]. In cultured cells facing ER stress, expression of both proteins is down-regulated in a post-transcriptional and p53-dependent manner that relies on regulatory elements located in their respective mRNA coding sequences [30,31] This points towards a shift in p53 activity during the Unfolded Protein Response (UPR) that is, at least in part, mediated at the level of mRNA translation. The following sections describe this activity of p53 and the associated physiological consequences
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