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Identification of targets specifically regulated by a 'super hybrid p53'

ABSTRACT: p63, like its homologue, the tumor suppressor p53, is also able to induce apoptosis in several cancer cell types. p53 family proteins are composed of three characteristic domains which are: 1) an N-terminal transactivation domain (TAD); 2) a central DNA-binding domain (DBD); and 3) an oligomerization domain (OD). In this study, we constructed recombinant adenoviruses containing hybrid genes composed of fragments of p53 and TAp63γ genes by connecting coding sequences of their three functional domains. The potency of tumor growth suppression of these hybrid molecules was evaluated using in vitro and in vivo models. One of the p53-p63 hybrid molecules, p63-53O, was observed to be the most potent activator of human cancer cells to apoptosis when compared to the p53, TAp63γ or several alternative p53-p63 hybrid molecules. p63-53O hybrid is composed of TAD and DBD of TAp63γ and OD of p53. In an effort to identify specific targets regulated by pro-apoptotic hybrid p63-53O, we next performed Affymetrix Genechip analysis and compared expression patterns in a human osteosarcoma cell line Saos-2 transfected separately with Ad-p53, Ad-TAp63γ and Ad-p63-53O.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35512 | GEO | 2012/02/04

SECONDARY ACCESSION(S): PRJNA152323

REPOSITORIES: GEO

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Identification of targets specifically regulated by a 'super hybrid p53'

Project description:p63, like its homologue, the tumor suppressor p53, is also able to induce apoptosis in several cancer cell types. p53 family proteins are composed of three characteristic domains which are: 1) an N-terminal transactivation domain (TAD); 2) a central DNA-binding domain (DBD); and 3) an oligomerization domain (OD). In this study, we constructed recombinant adenoviruses containing hybrid genes composed of fragments of p53 and TAp63γ genes by connecting coding sequences of their three functional domains. The potency of tumor growth suppression of these hybrid molecules was evaluated using in vitro and in vivo models. One of the p53-p63 hybrid molecules, p63-53O, was observed to be the most potent activator of human cancer cells to apoptosis when compared to the p53, TAp63γ or several alternative p53-p63 hybrid molecules. p63-53O hybrid is composed of TAD and DBD of TAp63γ and OD of p53. In an effort to identify specific targets regulated by pro-apoptotic hybrid p63-53O, we next performed Affymetrix Genechip analysis and compared expression patterns in a human osteosarcoma cell line Saos-2 transfected separately with Ad-p53, Ad-TAp63γ and Ad-p63-53O. Saos-2 osteosarcoma cells were either transduced with adenoviral vectors expressing p53, TAp63gamma, p53-p63 hybrid (p63-53O), or GFP. After 24 hours, mRNA was isolated and analyzed by hybridization to Affymetrix HG-U133 plus 2 arrays.

2012-02-04 | E-GEOD-35512 | biostudies-arrayexpress

Gene expression profiles induced by knockdown and overexpression of p63 variants in MCF-10A mammary epithelial cell line

Project description:p63 is critical for epithelial development yet little is known about the transcriptional programmes it regulates. The p63 transactivating (TA) isoforms contain an amino-terminal exon that encodes a p53-like transactivation domain, whereas ÎN-isoforms lack this domain but contain the common DNA binding domain (DBD), suggesting that TAp63 and ÎNp63 isoforms may have opposing functions. By characterising transcriptional changes and cellular effects following modulation of p63 expression, we have defined a vital role for p63 in cellular adhesion. Knockdown of p63 expression caused downregulation of cell adhesion-associated genes, cell detachment and anoikis in mammary epithelial cells and keratinocytes. Conversely, overexpression of the TAp63Î³ or ÎNp63Î± isoforms of p63 upregulated cell adhesion molecules, increased cellular adhesion and conferred resistance to anoikis. Total RNA was isolated 48 h after retroviral or adenoviral infection and was subjected to reverse transcription, labelling and hybridization. The knockdown samples were performed in duplicate with shRNA vector control, shRNA targetting all isoforms of p63 (shDBD) and shRNA targetting p63 isoforms containing the transactivating (TA) domains. The overexpression samples were performed in triplicate with vector control, overexpression of the ÎNp63Î± isoform, and overexpression of the TAp63Î³ isoforms.

2010-03-23 | E-GEOD-20286 | biostudies-arrayexpress

Gene expression signatures in HuH7 cells transfected with super hybrid p53 version 2.

Project description:The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p63 and p73. However, the regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we created a p63/p53 hybrid molecule, named p63-53O, which comprises the transcriptional activation and DNA-binding domains of TAp63? and the oligomerization domain of p53. In this study, we generated a series of p63-53O derivatives and developed an advanced hybrid molecule named “Super Hybrid p53 (SHp53).” SHp53 efficiently transactivated several proapoptotic genes, including CASP10, KCNK3, and PYCARD, compared with p53. Moreover, the silencing of these proapoptotic genes partially abolished the apoptotic response to SHp53 in human cancer cells. The potency of SHp53 for suppressing tumorigenesis was also evaluated using in vivo models. Thus, our results identify a better p63/p53 hybrid molecule for the development of anti-cancer therapies. HuH-7 human hepatocellular carcinoma cells were either transduced with adenoviral vectors expressing p53, TAp63gamma, p53-p63 hybrid (super hybrid p53 version 2, p63-53O-FL), or lacZ. After 24 hours, total RNA was isolated and analyzed by hybridization to Agilent-028004 SurePrint G3 Human GE 8x60K Microarray.

2013-05-23 | E-GEOD-42493 | biostudies-arrayexpress

Gene expression signatures in HuH7 cells transfected with super hybrid p53 version 2.

Project description:The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p63 and p73. However, the regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we created a p63/p53 hybrid molecule, named p63-53O, which comprises the transcriptional activation and DNA-binding domains of TAp63γ and the oligomerization domain of p53. In this study, we generated a series of p63-53O derivatives and developed an advanced hybrid molecule named “Super Hybrid p53 (SHp53).” SHp53 efficiently transactivated several proapoptotic genes, including CASP10, KCNK3, and PYCARD, compared with p53. Moreover, the silencing of these proapoptotic genes partially abolished the apoptotic response to SHp53 in human cancer cells. The potency of SHp53 for suppressing tumorigenesis was also evaluated using in vivo models. Thus, our results identify a better p63/p53 hybrid molecule for the development of anti-cancer therapies.

2013-05-23 | GSE42493 | GEO

Gene expression profiles induced by knockdown and overexpression of p63 variants in MCF-10A mammary epithelial cell line

2010-03-12 | GSE20286 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA2]

Project description:Mutations that occur within the oligomerization domain (OD) of the tumor suppressor p53 generally abolish p53 tetramerization and are associated with increased cancer susceptibility in Li-Fraumeni syndrome (LFS). Despite their prevalence, the impact of OD-mutant p53 proteins in cancer, especially beyond a loss of canonical p53 activity, has not been well elucidated. We sought to delineate the gain-of-function (GOF) vs. loss-of-function (LOF) activities of OD-mutant p53, specifically focusing on the LFS tumor-derived p53(A347D) variant. We obtained LFS patient-derived dermal fibroblasts heterozygous for the mutation and generated an allelic series of U2OS cancer cell lines expressing wild-type p53, heterozygous (p53+/AD) or homozygous (p53AD/AD) mutant p53 or no p53 (p53 KO). In contrast to wild-type p53, mutant p53(A347D) exclusively forms dimers in both fibroblasts and cancer cells and has lost the ability to bind and transactivate the majority of canonical p53 target genes, which yields comparable tumorigenic properties between mutant p53 and p53 KO cells. Mutant p53(A347D), however, displays neomorphic activities. Glycolysis and oxidative phosphorylation pathways are enriched in cells bearing p53(A347D) relative to both wild-type p53 and p53 KO cells. Furthermore, dimeric mutant p53 induces striking mitochondrial network aberration and preferentially associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Ultimately, we describe dimeric mutant p53 as wielding a double-edged sword: driving tumorigenesis through LOF while gaining enhanced apoptogenic activity, thereby providing a potential basis for select therapeutic approaches.

2023-04-20 | GSE226406 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [RNA1]

2023-04-20 | GSE226389 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP2]

2023-04-20 | GSE226384 | GEO

Li-Fraumeni Syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [ChIP 1]

2023-04-20 | GSE226371 | GEO

Colon cancer stem cell over-expressing TAp63α

Project description:p63, a member of p53 family, is transcribed in different variants, containing (TA) or lacking (N) the N-terminal transactivation domain. Although the proteins of p53 family share high sequence and structural similarities, distinct functions for p63 are emerging. Here we provided a quantitative proteomic analysis by stable isotope dimethyl labeling of colon cancer stem cells over-expressing TAp63α in order to investigate the cellular pathways modulated by this p63 isoform.

2014-03-17 | PXD000768 | Pride

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