p53 Isoforms: Key Regulators of the Cell Fate Decision

Joruiz, Sebastien M; Bourdon, Jean-Christophe

doi:10.1101/cshperspect.a026039

Cited by 147 publications

(185 citation statements)

References 119 publications

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“…Finally, recent data from the D122p53 mouse has shown that there is also cooperativity as D122p53 enhanced the survival of p53-mutant mice (25) and full-length p53 increased the ability of D122p53 to promote cell migration (16). This is consistent with the isoforms functioning in a complex network to determine cell fate outcomes (17).…”

Section: Introductionsupporting

confidence: 67%

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A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

et al. 2016

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TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53a_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCRbased methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151-9. Ó2016 AACR.

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Section: Introductionsupporting

confidence: 67%

“…Multiple studies have now shown that p53 isoforms have distinct functions and frequently contribute to diseases including cancer (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Elevated expression of the D40p53 isoform has been associated with metastatic melanoma and triple-negative breast cancers (7,19).…”

Section: Introductionmentioning

confidence: 99%

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

et al. 2016

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“…In the last decade, p53 has been found to encode a large number of isoforms2425. It has demonstrated that p53 isoforms can modulate p53 functions either synergistically or antagonistically26.…”

Section: Discussionmentioning

confidence: 99%

p53 isoform Δ133p53 promotes efficiency of induced pluripotent stem cells and ensures genomic integrity during reprogramming

Gong

Pan

Chen

et al. 2016

Sci Rep

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Human induced pluripotent stem (iPS) cells have great potential in regenerative medicine, but this depends on the integrity of their genomes. iPS cells have been found to contain a large number of de novo genetic alterations due to DNA damage response during reprogramming. Thus, to maintain the genetic stability of iPS cells is an important goal in iPS cell technology. DNA damage response can trigger tumor suppressor p53 activation, which ensures genome integrity of reprogramming cells by inducing apoptosis and senescence. p53 isoform Δ133p53 is a p53 target gene and functions to not only antagonize p53 mediated apoptosis, but also promote DNA double-strand break (DSB) repair. Here we report that Δ133p53 is induced in reprogramming. Knockdown of Δ133p53 results 2-fold decrease in reprogramming efficiency, 4-fold increase in chromosomal aberrations, whereas overexpression of Δ133p53 with 4 Yamanaka factors showes 4-fold increase in reprogamming efficiency and 2-fold decrease in chromosomal aberrations, compared to those in iPS cells induced only with 4 Yamanaka factors. Overexpression of Δ133p53 can inhibit cell apoptosis and promote DNA DSB repair foci formation during reprogramming. Our finding demonstrates that the overexpression of Δ133p53 not only enhances reprogramming efficiency, but also results better genetic quality in iPS cells.

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“…These transcripts encode protein isoforms that differ from canonical p53 by the lack of amino-terminal domains (D40p53, lacking residues 1 -39; D133p53, lacking residues 1-132) or by alternative carboxyl-terminal domains ( p53b and p53g) (Courtois et al 2004;Khoury and Bourdon 2010;Marcel et al 2011). Although the precise functions of these isoforms is still poorly understood, there is strong experimental evidence that amino-terminally truncated p53 variants may counteract the suppressor functions of full-length p53 protein (reviewed in Marcel et al 2011; see also Joruiz and Bourdon 2016).…”

Section: Toward An Unbiased Somatic Tp53 Mutation Spectrummentioning

confidence: 99%

SomaticTP53Mutations in the Era of Genome Sequencing

Hainaut

Pfeifer

2016

Cold Spring Harb Perspect Med

202

137

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Amid the complexity of genetic alterations in human cancer, TP53 mutation appears as an almost invariant component, representing by far the most frequent genetic alteration overall. Compared with previous targeted sequencing studies, recent integrated genomics studies offer a less biased view of TP53 mutation patterns, revealing that .20% of mutations occur outside the DNA-binding domain. Among the 12 mutations representing each at least 1% of all mutations, five occur at residues directly involved in specific DNA binding, four affect the tertiary fold of the DNA-binding domain, and three are nonsense mutations, two of them in the carboxyl terminus. Significant mutations also occur in introns, affecting alternative splicing events or generating rearrangements (e.g., in intron 1 in sporadic osteosarcoma). In aggressive cancers, mutation is so common that it may not have prognostic value (all these cancers have impaired p53 function caused by mutation or by other mechanisms). In several other cancers, however, mutation makes a clear difference for prognostication, as, for example, in HER2-enriched breast cancers and in lung adenocarcinoma with EGFR mutations. Thus, the clinical significance of TP53 mutation is dependent on tumor subtype and context. Understanding the clinical impact of mutation will require integrating mutationspecific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity.

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p53 Isoforms: Key Regulators of the Cell Fate Decision

Cited by 147 publications

References 119 publications

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

p53 isoform Δ133p53 promotes efficiency of induced pluripotent stem cells and ensures genomic integrity during reprogramming

SomaticTP53Mutations in the Era of Genome Sequencing

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