The p53 tumor suppressor and its key regulator MDM2 play essential roles in development, ageing, cancer, and cellular stress responses in mammals. Following DNA damage, MDM2 interacts with p53 mRNA in an ATM kinase-dependent fashion and stimulates p53 synthesis, whereas under normal conditions, MDM2 targets the p53 protein for degradation. The peptide- and RNA motifs that interact with MDM2 are encoded by the same conserved BOX-I sequence, but how these interactions have evolved is unknown. Here, we show that a temperature-sensitive structure in the invertebrate Ciona intestinalis (Ci) p53 mRNA controls its interaction with MDM2. We also show that a nonconserved flanking region of Ci-BOX-I domain prevents the p53-MDM2 protein-protein interaction. These results indicate that the temperature-regulated p53 mRNA-MDM2 interaction evolved to become kinase regulated in the mammalian DNA damage response. The data also suggest that the negative regulation of p53 by MDM2 via protein-protein interaction evolved in vertebrates following changes in the BOX-I flanking sequence.
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, ∆40p53, p53∆N40), 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.Cancers 2020, 12, 401 2 of 17 carcinomas, and leukemia, particularly in children and young adults [6]. Patients with this syndrome generally express both the mutant and wild-type (p53wt) forms of p53 in all tissues. During cancer progression, the wild-type activity of the protein is often lost, either due to the occurrence of dominant-negative (DNE) inhibitor mutations, to a gain of function (GOF) mutation that favors cancer progression, or to a direct loss of p53wt allele, a phenomenon known as loss of heterozygosity (LOH) [1,6]. The important handicap imposed by expressing half of the normal amount of fully active p53 in Li-Fraumeni patients [1,7] highlights the sensitivity of the pathway to small changes in p53 levels.In tumor cells containing wild-type TP53 gene, p53 activity might be compromised through different mechanisms. A well-known example constitutes the inhibitory interaction of p53 with proteins from cancer-associated virus, such as the T antigen from SV40 [8,9], adenovirus E1b protein [10] and the E6 protein from human papilloma virus (HPV) types 16 and 18 [11,12]. Overexpression of cellular regulators such as Mouse double minute 2 homolog MDM2 [13] and its homolog MDMX (MDM4) [14] can also suppress p53 activity and therefore have oncogenic potential. Under normal conditions, MDM2 and MDMX bind the conserved BOX-I motif in the N-terminus of p53 and mask its transactivation (TA) domain [13][14][15][16]. Moreover, MDM2, but not MDMX, possesses an E3-ubiquitin ligase activity that relies on its C-terminal RING domain, and targets p53 for 26S-dependent proteasomal degradation [17].p53 activation during the DNA damage response (DDR) has...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.