Modulation of alternative splicing contributes to cancer development: focusing on p53 isoforms, p53β and p53γ

Solomon, Hilla; Sharon, Michal; Rotter, Varda

doi:10.1038/cdd.2014.99

Cited by 24 publications

(20 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite all these years of exciting investigations, many controversial issues remain to be fully clarified to elucidate the physiological and pathological roles of the p53. This wide complexity raises from different aspects and facts, including regulation by proteasomal degradation [ 54 , 94 – 98 ] and micro-RNA [ 99 – 107 ] or the existence of numerous splicing variants [ 108 – 116 ]. Accordingly, significant efforts are under way to harness its potential practical application for human diseases, especially with regard to cancer [ 117 – 126 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic pathways regulated by TAp73 in response to oxidative stress

Agostini

Annicchiarico-Petruzzelli

Melino

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Reactive oxygen species are involved in both physiological and pathological processes including neurodegeneration and cancer. Therefore, cells have developed scavenging mechanisms to maintain redox homeostasis under control. Tumor suppressor genes play a critical role in the regulation of antioxidant genes. Here, we investigated whether the tumor suppressor gene TAp73 is involved in the regulation of metabolic adaptations triggered in response to oxidative stress. H2O2 treatment resulted in numerous biochemical changes in both control and TAp73 knockout (TAp73−/−) mouse embryonic fibroblasts, however the extent of these changes was more pronounced in TAp73−/− cells when compared to control cells. In particular, loss of TAp73 led to alterations in glucose, nucleotide and amino acid metabolism. In addition, H2O2 treatment resulted in increased pentose phosphate pathway (PPP) activity in null mouse embryonic fibroblasts. Overall, our results suggest that in the absence of TAp73, H2O2 treatment results in an enhanced oxidative environment, and at the same time in an increased pro-anabolic phenotype. In conclusion, the metabolic profile observed reinforces the role of TAp73 as tumor suppressor and indicates that TAp73 exerts this function, at least partially, by regulation of cellular metabolism.

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolic pathways regulated by TAp73 in response to oxidative stress

Agostini

Annicchiarico-Petruzzelli

Melino

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…The manipulation of p53 isoforms using splicing-factor inhibitors, autophagy inhibitors, DNA damage, p53 isoform overexpression, and/or siRNA targeting, specifically the p53 isoforms, enables the triggering of different cell-fate outcomes in response to the same damage Horikawa et al 2014;Marcel et al 2014;Gong et al 2015). Mechanistically, p53 isoforms oligomerize so that, for example, the oligomers composed of p53b and p53a regulate different p53-responsive genes than the ones composed of p53g and p53a or D133p53a and p53a (Fujita et al 2009;Aouba et al 2011;Bernard et al 2013;Marcel et al 2014;Solomon et al 2014). p53 isoform expression is cell-type-specific and several p53 isoforms are always concomitantly coexpressed or are mutually exclusive (Fig.…”

Section: Regulation Of Human P53 Isoform Expression/activitiesmentioning

confidence: 99%

p53 Isoforms: Key Regulators of the Cell Fate Decision

Joruiz

Bourdon

2016

Cold Spring Harb Perspect Med

137

169

View full text Add to dashboard Cite

It is poorly understood how a single protein, p53, can be responsive to so many stress signals and orchestrates very diverse cell responses to maintain/restore cell/tissue functions. The uncovering that TP53 gene physiologically expresses, in a tissue-dependent manner, several p53 splice variants (isoforms) provides an explanation to its pleiotropic biological activities. Here, we summarize a decade of research on p53 isoforms. The clinical studies and the diverse cellular and animal models of p53 isoforms (zebrafish, Drosophila, and mouse) lead us to realize that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the coexpressed p53 isoforms and that unbalancing expression of different p53 isoforms leads to cancer, premature aging, (neuro)degenerative diseases, inflammation, embryo malformations, or defects in tissue regeneration. Cracking the p53 isoforms' code is, thus, a necessary step to improve cancer treatment. It also opens new exciting perspectives in tissue regeneration.

show abstract

“…These findings suggested that novel isoform-based gene diagnosis and biological therapy may potentially be developed (10,11,13,15,16,(20)(21)(22)(23). In previous studies, all p53 isoforms were detected in tissue from superficial gastritis, atrophic gastritis, para-cancerous area, to advanced gastric carcinoma (24,25).…”

mentioning

confidence: 78%

Role of p53β in the inhibition of proliferation of gastric cancer cells expressing wild-type or mutated p53

Zhang

et al. 2012

Molecular Medicine Reports

View full text Add to dashboard Cite

p53 is a tumor suppressor gene whose mutation is highly associated with tumorigenesis. The present study investigated the role of p53β in the inhibition of proliferation of gastric cancer cell lines expressing wild-type or mutated p53. Wild-type p53 is expressed in MKN45 cells, but deleted in KATOIII cells, whereas mutated p53 is expressed in SGC7901 cells. The mRNA expression levels of p53β and Δ133p53 were detected in MKN45, SGC-7901 and KATOIII gastric cancer cell lines using nested polymerase chain reaction (PCR). The mRNA expression levels of p53, p53β and B-cell lymphoma 2-associated X protein (Bax) were detected in the MKN45 and SGC-7901 cells following treatment with cisplatin by reverse transcription-PCR. The inhibition of cellular proliferation following treatment with cisplatin was measured by MTT assay. The results of the present study demonstrated that both p53β and Δ133p53 mRNA were expressed in the MKN45 cells, whereas only p53β mRNA was expressed in the SGC7901 cells. No expression of p53β or Δ133p53 mRNA was detected in the KATOIII cells. Following treatment with cisplatin, the number of both MKN45 and SGC-7901 cells was significantly reduced (P<0.001). In the MKN45 cells, p53β, p53 and Bax mRNA expression levels gradually increased with the dose of cisplatin, and the expression of p53β was positively correlated with the expression of p53 (tr=6.358, P<0.05) and Bax (tr=8.023, P<0.05). In the SGC-7901 cells, the expression levels of p53β, p53 and Bax mRNA did not alter with the dose of cisplatin, and the expression of p53β was positively correlated to the expression of p53 (tr=26.41, P<0.01) but not that of Bax. The present study identified the different roles of the p53β isoform in gastric cancer cells with different p53 backgrounds. Enhanced knowledge regarding the p53 status is required for the development of specific biological therapies against gastric cancer.

show abstract

Modulation of alternative splicing contributes to cancer development: focusing on p53 isoforms, p53β and p53γ

Cited by 24 publications

References 19 publications

Metabolic pathways regulated by TAp73 in response to oxidative stress

Metabolic pathways regulated by TAp73 in response to oxidative stress

p53 Isoforms: Key Regulators of the Cell Fate Decision

Role of p53β in the inhibition of proliferation of gastric cancer cells expressing wild-type or mutated p53

Contact Info

Product

Resources

About