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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 01, 2012 |
| Title |
Systemic elevation of PTEN induces a tumor suppressive metabolic state |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect.
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| Overall design |
In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.
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| Contributor(s) |
Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VC, Anastasiou D, Ito K, Sasaki A, Rameh L, Carracedo A, Vander Heiden MG, Cantley LC, Pinton P, Haigis MC, Pandolfi PP |
| Citation(s) |
22401813 |
| Submission date |
Feb 09, 2012 |
| Last update date |
Aug 06, 2018 |
| Contact name |
Manoj Bhasin |
| Phone |
6176670009
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| Organization name |
Beth Israel Deaconess Medical Center
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| Street address |
330 Brookline Avenue RN 380E
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL11180 |
[HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate |
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| Samples (6)
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| GSM873270 |
Mouse embryonic fibroblasts wt #1 (biological rep 1) |
| GSM873271 |
Mouse embryonic fibroblasts wt #2 (biological rep 2) |
| GSM873272 |
Mouse embryonic fibroblasts wt #7 (biological rep 3) |
| GSM873273 |
Mouse embryonic fibroblasts tg #3 (biological rep 1) |
| GSM873274 |
Mouse embryonic fibroblasts tg #5 (biological rep 2) |
| GSM873275 |
Mouse embryonic fibroblasts tg #8 (biological rep 3) |
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| Relations |
| BioProject |
PRJNA152443 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE35670_RAW.tar |
15.1 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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