Alternative Mechanisms of p53 Action During the Unfolded Protein Response

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, ∆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...

The Leloir Cycle in Glioblastoma: Galactose Scavenging and Metabolic Remodeling

“…Physiological stresses, including glucose starvation, hypoxia, increased temperature, and an interruption in the supply of UDP-hexoses, activate the ER sensors, ATF6, PERK, and IRE1. ER stress signaling, via PERK, can lead to increased levels of TIGAR (TP53-induced glycolysis and apoptosis regulator) via increases in canonical p53 and the p53/p47 variant [ 46 , 47 , 48 , 49 ]. Additionally, ER stress can activate the IRE1/Xbp1s signaling cascades and elevate the Leloir pathway enzymes GALE and GALK [ 50 ].…”

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

“…Based on several recent studies, p53 mutant cancer cells have higher levels of IRE1, and the activation of XBP1 was induced in the absence of stress and activation and contributes to higher malignancy and the aggressive phenotype of the tumors [ 80 ]. It addition, it has been reported that p53 is involved in the regulation of cellular homeostasis during the UPR [ 81 ]. Therefore, a difference in UPR between U87 and U251 in the presence of Simva–TMZ treatment could be correlated to the p53 status in these cells.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Compared to healthy elderly controls, p53 in AD patients exhibited a 100% increase in p53 in the superior temporal gyrus, and induced the phosphorylation of tau in HEK293a cells in vitro [ 728 ]. Dysregulation of p53 such as unfolded p53 caused by oxidative stress [ 780 ] is a reliable biomarker for AD [ 781 , 782 ], whereas overexpression of the truncated p53 isoform p47 (Δ40p53 or p44) [ 783 ] in mice accelerated aging and increased tau fibrillation [ 782 , 784 , 785 ]. Tau was recently reported to have increased wild-type p53 expression post-translationally through the abnormal modification of MDM2, the E3 ubiquitin ligase which negatively regulates p53 [ 786 , 787 , 788 , 789 ].…”