The p53 mRNA: an integral part of the cellular stress response

Hároníková, Lucia; Olivares‐Illana, Vanesa; Wang, Lixiao; Karakostis, Konstantinos; Chen, Sa; Fåhræus, Robin

doi:10.1093/nar/gkz124

Cited by 60 publications

(74 citation statements)

References 163 publications

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“…The regulation of p53 stabilisation is largely considered to be post‐translational, so that the transcriptional regulation of p53 in malignant tumours has often been neglected. But TP53 mRNA has been shown to play important roles in cellular stress responses and analysis of TP53 mRNA may provide relevant additional insights into mechanisms of heterogeneity. The detection of robust Trp53 / TP53 mRNA in TACs of rapidly renewing tissues in murine SCC and precursor lesions and in human HT29 colon cancer xenograft tumours indicates that mRNA can be evaluated using currently available methods .…”

Section: Combined P53 Protein/mrna Detection and The Use Of Mutant‐spmentioning

confidence: 99%

Intratumour heterogeneity of p53 expression; causes and consequences

Xue

Luis

Lane

2019

The Journal of Pathology

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Genomic alterations in different types of cancer have been identified by comprehensive sequencing methodologies, revealing TP53 as the most frequently mutated gene across the majority of human cancer types. Cytotoxic treatments are still major cancer therapy strategies but cancer recurrence due to therapy resistance is a major challenge. Resistant cell populations may be associated with TP53 mutant clones exhibiting abnormal p53 expression patterns in tumours. Given data that levels of mutant p53 influence cancer cell growth and survival, understanding the mechanisms underlying intratumour heterogeneity of p53 can be exploited to design strategies that improve patient survival. The patterns of p53 protein examined by immunohistochemistry of both premalignant and malignant tissues are complex, ranging from intense staining of all tumour cell nuclei to complete absence of staining and with many intermediate phenotypes. Animal models that express only mutant proteins and adoption of international standards for terminology have brought greater clarity to understanding the causes of variation and are at the same time demonstrating the utility of p53 in oncology. In addition to p53 mutation, MDM2 and chaperone activities, gene copy number and TP53 mRNA levels linked to proliferative activity and differentiation are all now established as causes of variation in p53 staining, with clinical implications. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Combined P53 Protein/mrna Detection and The Use Of Mutant‐spmentioning

confidence: 99%

Intratumour heterogeneity of p53 expression; causes and consequences

Xue

Luis

Lane

2019

The Journal of Pathology

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“…This role emerges as an interesting target since it offers a new way for p53 to dictate cell fate during ER stress, as exemplified by the cell cycle arrest and apoptosis induced by suppression of p21 and BiP, respectively (Table 1) [31,58,98]. Importantly, translational control of specific mRNA targets also provides a physiological role for p53's RNA binding activity [70,98], which merits more attention. In addition, it illustrates how cells can differentially modulate p53 activity in response to a defined cellular stress pathway in order to trigger a specific and suitable cell-biological outcome by inducing the expression of different isoforms with apparent distinctive functions ( Figure 1 and Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Several IRES-transacting factors (ITAFs) were shown to bind to this region and tune the expression of both p53fl and p47 [66]. Moreover, other numerous proteins apart from ITAFs were shown to interact throughout the p53 mRNA in response to different signaling pathways and control the RNA stability, translation efficiency or alternative initiation of translation, emphasizing the seminal role of p53 mRNA as a platform that orchestrates the p53 pathway [70][71][72].…”

Section: Induction Of the P47 Isoform During Er Stressmentioning

confidence: 99%

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

Fusee

Marı́n

Fåhræus

et al. 2020

Cancers

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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...

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“…The p53 tumor suppressor protein plays a multifunctional regulatory role in several physiological processes, including the cell cycle, DNA repair, and apoptosis (reviewed in [64]). Its gene, TP53, belongs to the most frequently mutated genes in cancer [65].…”

Section: Brca1 In Nucleotide Excision Repair In Breast Cancermentioning

confidence: 99%

Interplay between BRCA1 and GADD45A and Its Potential for Nucleotide Excision Repair in Breast Cancer Pathogenesis

Pietrasik

Zajac

Morawiec

et al. 2020

IJMS

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A fraction of breast cancer cases are associated with mutations in the BRCA1 (BRCA1 DNA repair associated, breast cancer type 1 susceptibility protein) gene, whose mutated product may disrupt the repair of DNA double-strand breaks as BRCA1 is directly involved in the homologous recombination repair of such DNA damage. However, BRCA1 can stimulate nucleotide excision repair (NER), the most versatile system of DNA repair processing a broad spectrum of substrates and playing an important role in the maintenance of genome stability. NER removes carcinogenic adducts of diol-epoxy derivatives of benzo[α]pyrene that may play a role in breast cancer pathogenesis as their accumulation is observed in breast cancer patients. NER deficiency was postulated to be intrinsic in stage I of sporadic breast cancer. BRCA1 also interacts with GADD45A (growth arrest and DNA damage-inducible protein GADD45 alpha) that may target NER machinery to actively demethylate genome sites in order to change the expression of genes that may be important in breast cancer. Therefore, the interaction between BRCA1 and GADD45 may play a role in breast cancer pathogenesis through the stimulation of NER, increasing the genomic stability, removing carcinogenic adducts, and the local active demethylation of genes important for cancer transformation.

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The p53 mRNA: an integral part of the cellular stress response

Cited by 60 publications

References 163 publications

Intratumour heterogeneity of p53 expression; causes and consequences

Intratumour heterogeneity of p53 expression; causes and consequences

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

Interplay between BRCA1 and GADD45A and Its Potential for Nucleotide Excision Repair in Breast Cancer Pathogenesis

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