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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Yasushi Sasaki

PROVIDER: E-GEOD-42493 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

miRNA array after p63 knock down in human squamous cell carcinoma

Project description:A central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct, p53-independent roles in development and cancer: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. Here, we identify a new and physiologically important mechanism of p63/p73 cross-talk which governs the balance between pro-survival and pro-apoptotic programs in both human and murine squamous cell carcinoma. Through comprehensive profiling of p63-regulated microRNAs (miRs), we identified a subset which target p73 for inhibition, including miR-193a-5p, a direct endogenous transcriptional target repressed by p63 and activated by pro-apoptotic p73 isoforms in both normal cells and tumor cells in vivo. Consequently, chemotherapy treatment causes p63/p73-dependent induction of this miR, thereby limiting chemosensitivity due to miR-mediated feedback control of p73. We demonstrate that interrupting this feedback by inhibiting miR-193a suppresses tumor cell viability and induces dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, miR-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition provides a new therapeutic opportunity in p53-deficient tumors. Knockdown of endogenous p63 by p63-directed or control lentiviral shRNA in JHU-029 human SCC cells at 48h, in duplicate experiments. Array analysis showing the fold-change and direction of change for all miRs regulated > 1.5-fold in p63-ablated versus control samples

2010-11-23 | E-GEOD-25524 | biostudies-arrayexpress

miRNA array after p63 knock down in human squamous cell carcinoma

2010-11-23 | GSE25524 | GEO

Transcription profiling of human steosarcoma cell line Saos-2 infected separately with p53 and TAp73beta expressing adenovirus to identify targets specifically regulated by TAp73

Project description:The p53 family consists of three members, p53, p73, and p63. These proteins share a high degree of amino-acid sequence similarity and major functional domains. The p53 gene, the first member of the family to be identified, is the most frequent target gene for genetic alterations in human cancers. In contrast, p73 and p63 are mainly involved in normal development and differentiation. These differences among the p53 family are likely to depend on activation or repression of different sets of target genes. In this study, to identify targets specifically regulated by p73, we performed microarray analysis and compared expression patterns in a human steosarcoma cell line Saos-2 infected separately with p53 and TAp73beta expressing adenovirus. Experiment Overall Design: Saos2 osteosarcoma cells were infected with p53, TAp73beta expressing or control adenovirus for 24 h and then harvested.

2008-11-15 | E-GEOD-13504 | biostudies-arrayexpress

Transcription profiling by array of human p73 over-expressing H1299 cells

Project description:The integral role of p53 in tumor suppression has promted many laboratories to perform extensive analyses of signaling pathways downstream of the p53 family of sequence-specific DNA binding transcription factors (p53 and its homologs p63 and p73). Despite the ability of p73 to regulate many p53 family target genes, little is known about the specific pathways that modulate p73 during development, tumorigenesis and tumor therapy. In this study we present a gene signature-based approach for connecting signaling pathways to transcription factors, as exemplified by p73. We generated a p73 gene signature by integrating whole-genome chromatin immunoprecipitation and expression profiling. Experiment Overall Design: H1299 lung carcinoma cells were infected with p73 expressing or control adenovirus for 5 h and then harvested.

2008-10-20 | E-GEOD-11626 | biostudies-arrayexpress

Identification of targets specifically regulated by TAp73

2008-11-08 | GSE13504 | GEO

Expression data from p73 over-expression in H1299 cells

2008-08-06 | GSE11626 | GEO

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

ChIP-Seq of human H1299 lung carcinoma cells - genomic location data for ectopic p73

Project description:The integral role of p53 in tumor suppression has promted many laboratories to perform extensive analyses of signaling pathways downstream of the p53 family of sequence-specific DNA binding transcription factors (p53 and its homologs p63 and p73). Despite the ability of p73 to regulate many p53 family target genes, little is known about the specific pathways that modulate p73 during development, tumorigenesis and tumor therapy. In this study we present a gene signature-based approach for connecting signaling pathways to transcription factors, as exemplified by p73. We generated a p73 gene signature by integrating whole-genome chromatin immunoprecipitation and expression profiling. Experiment Overall Design: H1299 lung carcinoma cells were transduced with TAp73beta or GFP expressing adenoviruses. Microarray analysis (on the GFP and TAp73beta samples) and ChIPSeq analysis (on the TAp73beta sample) were performed to identify candidate p73 target genes.

2009-08-30 | E-GEOD-11672 | biostudies-arrayexpress

Identification of candidate p73 target genes

Project description:The integral role of p53 in tumor suppression has promted many laboratories to perform extensive analyses of signaling pathways downstream of the p53 family of sequence-specific DNA binding transcription factors (p53 and its homologs p63 and p73). Despite the ability of p73 to regulate many p53 family target genes, little is known about the specific pathways that modulate p73 during development, tumorigenesis and tumor therapy. In this study we present a gene signature-based approach for connecting signaling pathways to transcription factors, as exemplified by p73. We generated a p73 gene signature by integrating whole-genome chromatin immunoprecipitation and expression profiling. This SuperSeries is composed of the SubSeries listed below.

2008-08-06 | GSE11673 | GEO

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