p53 isoforms can regulate p53 transcriptional activity

Bourdon, Jean-Christophe; Fernandes, Kenneth; Murray-Zmijewski, F; Liu, Geng; Diot, Alexandra; Xirodimas, Dimitris P.; Saville, Mark K.; Lane, David P.

doi:10.1101/gad.1339905

Cited by 722 publications

(1,116 citation statements)

References 37 publications

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“…21 Moreover, D133p53a inhibits replicative senescence, p53-mediated apoptosis and G1 cell cycle arrest, without preventing p53-promoted G2 cell cycle arrest by regulating gene expression. [2][3][4][5] Altogether, it suggests that p53 isoforms have a key role in carcinogenesis. However, the role of p53 isoforms in angiogenesis was unknown.…”

Section: Discussionmentioning

confidence: 97%

“…Western blots were performed as previously described. 2 Primary antibodies were CM-1 and Sapu 2 for p53 and D133p53, respectively, 2A10 (Abcam, Cambridge, UK) for mdm2, TUB2.1 (Sigma-Aldrich) for b-Tubulin and AC-15 (Sigma-Aldrich) for b-Actin. Horseradish peroxidaseconjugated goat antibodies (Jackson ImmunoResearch, Baltimore, MD, USA), were used as secondary antibodies in immunoblots.…”

Section: Cells and Embryosmentioning

confidence: 99%

“…However, we have shown that the p53 gene expresses 12 protein isoforms. 1,2 Alternative splicing of intron 9 generates p53 isoforms bearing different C-terminal domains (a, b and g; Figure 1a). The presence of an alternative promoter in intron 4 generates D133p53 isoforms lacking the transactivation domain (TA) and part of the DNAbinding domain.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…2,3 A gain of expression of D133p53 mRNAs in human breast tumours versus normal breast tissue suggests a protumoural role of these isoforms. 2 Indeed, D113p53, the zebrafish ortholog of human D133p53a, is able to regulate wild-type p53 (WTp53) proapoptotic function. 3 This activity is conserved in human cells, as D133p53a can inhibit p53-mediated apoptosis and G1 cell cycle arrest without inhibiting p53-mediated G2 cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

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The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

et al. 2012

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The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53a), p53b and p53g) and D133p53 isoforms (D133p53a, D133p53b and D133p53g). The D133p53a isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of D133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for D133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The D133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each D133p53 isoform, we determined that D133p53a and D133p53g but not D133p53b, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of D133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of D133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with D133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.

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Section: Discussionmentioning

confidence: 97%

Section: Cells and Embryosmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

et al. 2012

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Small Molecule Inhibition of HDM2 Leads to p53-Mediated Cell Death in Retinoblastoma Cells

Elison¹

2006

Arch Ophthalmol

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To determine the efficacy of inducing p53mediated cell death in retinoblastoma cells by Nutlin 3A, a small molecule HDM2 inhibitor.Methods: Retinoblastoma cell lines WERI-RB-1 and Y79 were treated with Nutlin 3A. Cell viability assays, Western blot analyses, confocal microscopy, and flow cytometry were performed to measure cell survival, p53 protein levels, activation of downstream targets, and apoptosis. To determine whether the effects of Nutlin 3A were p53-dependent, cell viability assays were performed on Y79 cells expressing short interfering RNA (siRNA) against p53.Results: Nutlin 3A induced cell death in Y79 and WERI-RB-1 in the 5-to 10-µM dose range. Treated cells demonstrated increased protein levels of p53 and the p53 targets p21 and HDM2. Phosphorylation of p53-serine-15, a marker for activation of p53 via genotoxic mechanisms, was absent. Y79 cells expressing siRNA against p53 demonstrated resistance to Nutlin 3A.Conclusions: Nutlin 3A induced p53-mediated apoptosis in a dose-dependent, nongenotoxic fashion in 2 retinoblastoma cell lines.Clinical Relevance: Nutlin 3A is effective against retinoblastoma cells in a nongenotoxic manner. Because the mutagenic effects of radiation and chemotherapy may increase risks of secondary tumor formation, targeted p53 activation may be a safer alternative treatment for retinoblastoma in the future.

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Effect of p53 and its N‐terminally truncated isoform, Δ40p53, on breast cancer migration and invasion

et al. 2021

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Breast cancer is the most diagnosed malignancy in women, with over half a million women dying from this disease each year. In our previous studies, ∆40p53, an N‐terminally truncated p53 isoform, was found to be upregulated in breast cancers, and a high ∆40p53 : p53α ratio was linked with worse disease‐free survival. Although p53α inhibits cancer migration and invasion, little is known about the role of ∆40p53 in regulating these metastasis‐related processes and its role in contributing to worse prognosis. The aim of this study was to assess the role of ∆40p53 in breast cancer migration and invasion. A relationship between Δ40p53 and gene expression profiles was identified in oestrogen‐receptor‐positive breast cancer specimens. To further evaluate the role of Δ40p53 in oestrogen‐receptor‐positive breast cancer, MCF‐7 and ZR75‐1 cell lines were transduced to knockdown p53α or Δ40p53 and overexpress Δ40p53. Proliferation, migration and invasion were assessed in the transduced sublines, and gene expression was assessed through RNA‐sequencing and validated by reverse‐transcription quantitative PCR. Knockdown of both p53α and ∆40p53 resulted in increased proliferation, whereas overexpression of ∆40p53 reduced proliferation rates. p53α knockdown was also associated with increased cell mobility. ∆40p53 overexpression reduced both migratory and invasive properties of the transduced cells. Phenotypic findings are supported by gene expression data, including differential expression of LRG1, HYOU1, UBE2QL1, SERPINA5 and PCDH7. Taken together, these results suggest that, at the basal level, ∆40p53 works similarly to p53α in suppressing cellular mobility and proliferation, although the role of Δ40p53 may be cell context‐specific.

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p53 isoforms can regulate p53 transcriptional activity

Cited by 722 publications

References 37 publications

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

Small Molecule Inhibition of HDM2 Leads to p53-Mediated Cell Death in Retinoblastoma Cells

Effect of p53 and its N‐terminally truncated isoform, Δ40p53, on breast cancer migration and invasion

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