Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

The effect on gene expression by p53 family members and the knockdown of AKR1B10

ABSTRACT: To evaluate the effect on gene expression by p53 family members and AKR1B10, we overexpressed p53 family members in H1299 cells or knocked down AKR1B10 in HCT116 cells and evaluated the gene expression by microarray analysis. Gene expression was measured in H1299 cells infected with adenovirus expressing p53, p63g and p73b, and in HCT116 cells transfected with siRNAs targeting AKR1B10 and then treated with adriamycin.

ORGANISM(S): Homo sapiens

SUBMITTER: Masashi Idogawa

PROVIDER: E-GEOD-47096 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis.

Ohashi Tomoko T Idogawa Masashi M Sasaki Yasushi Y Suzuki Hiromu H Tokino Takashi T

Molecular cancer research : MCR 20131018 12

<h4>Unlabelled</h4>p53 is one of the most important tumor suppressor genes, and it is frequently inactivated in various cancers. p53 modulates various cellular functions, such as apoptosis and cell-cycle arrest via transcriptional regulation. Recently, p53 has been reported to be involved in a wide range of cellular metabolic pathways, including glycolysis, oxidative phosphorylation, glutaminolysis, and the antioxidant response. To understand the functional mechanism of p53, it is important to f ...[more]

PMID: 24140838

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Project description:This study is to find the cellular and molecular mechanisms by which a naturally-occurring deltaNp53 isoform causes accelerated aging in humans. The biological function of deltaNp53, which lacks only 40 N-terminal amino acids, represents an example of p53 as a regulator of mammalian aging. When expressed together with WTp53 in mice, ÎNp53 causes an aging phenotype such as shorter life span, reduced body mass, organ atrophy and osteoporosis. Because p53 must form a tetramer to regulate transcription, we generated p53 clones (based upon the structure of the native p53 tetramer) containing one ÎNp53 linked with one WTp53 to form a functional ÎNp53:WTp53 tetramer with 1:1 stoichiometry. Thus, our strategy ensured each p53 tetramer contained 2 ÎNp53 and 2 WTp53 proteins. Importantly, ÎNp53:WTp53 form stable tetramers, based upon gel filtration chromatography and structural analysis using electron microscopy. Furthermore, the ÎNp53:WTp53 tetramer activates transcription equally well compared with WTp53 tetramers in an in vitro reconstituted transcription system. Having verified the stoichiometry, stability, structure, and activity of these ÎNp53:WTp53 tetramers, here we used microarray analysis to compare global gene expression patterns in p53-null H1299 cells expressing either WTp53 or ÎNp53:WTp53. As expected, global gene expression was largely similar, since the differences between ÎNp53:WTp53 tetramers and WTp53 tetramers are slight: only 2 of 4 p53 proteins will be different in the ÎNp53:WTp53 tetramer. Among only several dozen genes that were selectively up- or down-regulated 2-fold or greater, many genes known to regulate mammalian aging were altered in cells expressing ÎNp53:WTp53, including insulin signaling pathway members (IRS1, INPP5D, PLK3, MAP3K1, FGF5) and regulators of glucose metabolism (SLC2A2, CRYAB, LRCH1). Expression of other key metabolic genes were also altered in cells expressing ÎNp53:WTp53 tetramers, suggesting that global me tabolic changes might contribute to ÎNp53:WTp53 pathology. In collaboration with Metabolon (Durham, NC), we identified approximately one hundred metabolites that were significantly up- or down-regulated in H1299 cells expressing ÎNp53:WTp53. The metabolome analysis was a powerful complement to the gene expression data, and further suggested that the mTOR pathway (e.g. across-the-board up-regulation of amino acid levels) and mitochondrial function (e.g. up-regulation of carnitine, important for a-oxidation of fatty acids) was altered in cells expressing ÎNp53:WTp53. These findings were subsequently validated using biochemical and cell-based approaches. Furthermore, whereas equal expression of ÎNp53 and WTp53 cause accelerated aging in mammals, due to alternative splicing and translation initiation ÎNp53 is a naturally-occurring isoform whose expression levels can change throughout the lifetime. Thus, the cellular and molecular mechanisms identified from this work will likely reflect changes common to normal, physiological aging. Comparison of global gene expression profiles in WTp53 or ÎNp53:WTp53 expressed H1299 RNA from FACS sorted GFP positive hybrid to Affymatrix Gene The exp 0, exp 4 and exp 5 are independent replicate/transfections/biological experiments. The exp d, exp e and exp f are control experiments.

Dataset Information

The effect on gene expression by p53 family members and the knockdown of AKR1B10

Publications

AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis.

Similar Datasets

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