How theTP53Family ProteinsTP63andTP73Contribute to Tumorigenesis: Regulators and Effectors

Candi, Eleonora; Agostini, Massimiliano; Melino, Gerry; Bernassola, Francesca

doi:10.1002/humu.22523

Cited by 127 publications

(109 citation statements)

References 157 publications

(198 reference statements)

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“…In vertebrates, shorter p53 isoforms can inhibit the apoptotic response to genotoxic stress. 2,16 We therefore assessed whether the overexpression of p53 isoforms altered the apoptotic response of ovarian follicle cells to ionizing radiation (IR). Isoform expression was induced using hsp70:GAL4 at time zero, adult females were irradiated with 4000 rads of gamma rays 2 h later, and ovaries labeled for cleaved Dcp-1 at 6 h after p53 expression as before.…”

Section: Resultsmentioning

confidence: 99%

“…1 The genomes of humans and other vertebrates encode two other p53 family members, p63 and p73. 2 Complicating the picture further, all three p53 family members encode a large number of protein isoforms, whose different activities in development and disease are still being defined. 2 Here, we investigate the apoptotic function of multiple protein isoforms encoded by the single p53 family member in the genetic model organism Drosophila melanogaster.…”

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confidence: 99%

“…4,[10][11][12] In recent years, the list of processes that p53 family members regulate has been growing and includes metabolism, autophagy, metastasis, stem cell division, and aging. 2,13 A current challenge for understanding the function of p53 family members is that they all encode a large number of protein isoforms, a property that is conserved among vertebrates and some invertebrates. 2,14 The human p53 gene encodes at least 12 different protein isoforms through the use of alternative promoters, splicing, and translation.…”

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confidence: 99%

“…2,13 A current challenge for understanding the function of p53 family members is that they all encode a large number of protein isoforms, a property that is conserved among vertebrates and some invertebrates. 2,14 The human p53 gene encodes at least 12 different protein isoforms through the use of alternative promoters, splicing, and translation. 15,16 Fulllength p53 protein contains an N-terminal transcriptional trans-activation domain (TAD), a DNA binding domain (DBD), an oligomerization domain (OD), and a C-terminal domain (CTD).…”

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confidence: 99%

“…8,9,[24][25][26][27][28][29][30][31] The p73 gene encodes over 14 protein isoforms. 2 Full-length p73 regulates neuronal stem cell maintenance, metabolism, spermatogenesis, cell cycle arrest, and apoptosis, whereas recent evidence suggests that elevated expression of short p73 isoforms contributes to several types of cancer. 32,33 The current data support that differential expression of p53, p63, and p73 isoforms in different developing tissues and tumors have important functional consequences, but the understanding of these complex interactions is far from complete.…”

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The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

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confidence: 99%

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confidence: 99%

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The function of Drosophila p53 isoforms in apoptosis

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ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

Gatti

Fernanda

Annicchiarico-Petruzzelli

et al. 2019

Molecular Oncology

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Squamous cell carcinoma ( SCC ) is a treatment‐refractory tumour which arises from the epithelium of diverse anatomical sites such as oesophagus, head and neck, lung and skin. Accumulating evidence has revealed a number of genomic, clinical and molecular features commonly observed in SCC of distinct origins. Some of these genetic events culminate in fostering the activity of ΔNp63, a potent oncogene which exerts its pro‐tumourigenic effects by regulating specific transcriptional programmes to sustain malignant cell proliferation and survival. In this review, we will describe the genetic and epigenetic determinants underlying ΔNp63 oncogenic activities in SCC , and discuss some relevant transcriptional effectors of ΔNp63, emphasizing their impact in modulating the crosstalk between tumour cells and tumour microenvironment ( TME ).

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Genetic variants in p53 signaling pathway genes predict chemotherapy efficacy in colorectal cancer

et al. 2019

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Background The murine double minute‐2 gene ( MDM2 ) was originally identified as predicting chemotherapy efficacy. However, little is known regarding the association between single nucleotide polymorphisms (SNPs) in the p53 signaling pathway and prognosis/chemotherapy sensitivity in colorectal cancer. Methods We analyzed the association between 111 SNPs in 22 p53 signaling pathway genes and both progression‐free survival (PFS) and disease control rate (DCR) using Cox regression and logistics regression analysis. The false discovery rate method was used for correction of multiple testing. Secondary structure was predicted by RNAfold. Expression qualitative trait locus analysis and mRNA expression differences were assessed using the GTEx and TCGA databases. Results We found that the rs747828 C allele of TP73 was significantly associated with reduced PFS (HR = 1.64, 95% CI = 1.27‐2.12, P = 2.00 × 10 −4 ) in the additive model. In the stratified analysis, the rs747828 C allele was significantly associated with both reduced PFS ( P = 1.40 × 10 −3 ) and DCR ( P = 1.82 × 10 −2 ) in oxaliplatin‐based chemotherapy. The secondary structure of TP73 was altered in response to different rs747828 genotypes. Although the rs747828 C allele was not associated with messenger RNA (mRNA) TP73 expression, it was significantly associated with increased mRNA TP73‐AS1 expression levels in sigmoid tissues. TP73 mRNA was significantly overexpressed in tumor tissues compared to adjacent normal tissues ( P = 2.36 × 10 −19 ). Conclusion Our findings indicate that functional genetic variants of TP73 mediate the response to chemotherapy in colorectal cancer.

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How theTP53Family ProteinsTP63andTP73Contribute to Tumorigenesis: Regulators and Effectors

Cited by 127 publications

References 157 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

Genetic variants in p53 signaling pathway genes predict chemotherapy efficacy in colorectal cancer

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