Project description:An Infinium microarray platform (HorvathMammalMethylChip320) was used to generate DNA methylation data from n=48 liver samples from mice. Treatment: encapsulated rapamycin treated or control mice
Project description:Dynamic mRNA gene expression from the wildtype YSBN6 during a rapamycin treatment (rapamycin-induced downshift). Rapamycin was added to yeast cells growing exponentially on glutamine as sole nitrogen source.
Project description:Drug resistance remains a major obstacle to successful cancer treatment. Here we use a novel approach to identify rapamycin as a glucocorticoid resistance reversal agent. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in Acute Lymphoblastic Leukemia (ALL) cells. The screen indicated the mTOR inhibitor rapamycin profile matched the signature of GC-sensitivity. We thus tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells, and found that it sensitized cells to glucocorticoid induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis, and that the combination of rapamycin and glucocorticoids has potential utility in ALL. Furthermore this approach represents a novel strategy for identification of promising combination therapies for cancer. Keywords: drug treatment
Project description:p73 is a p53 family transcription factor that plays critical roles during development and tumor suppression. We analyzed p73 activity using a combination of ChIP-on-Chip and gene expression profiling, both at baseline and after treatment with the mTOR inhibitor rapamycin. We report the first comprehensive analysis of p73 binding across the genome. Furthermore, we re-analyzed this p73 cistrome after perturbation with rapamycin, an inhibitor of mTOR and inducer of p73. Multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR.
Project description:The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid the adverse side-effects of clinical dosing regimes. Here we show a profound memory effect of brief rapamycin treatment. Brief, early adult treatment extended lifespan in Drosophila to the same degree as lifelong dosing. Lasting memory of earlier rapamycin treatment was mediated by elevated autophagy in enterocytes of the gut, accompanied by increased intestinal spermidine levels and improved structure and function of the ageing intestine. Brief elevation of autophagy itself induced a long-term increase in autophagy. In mice, short-term, 3-month treatment also induced a full memory effect, with enhanced autophagy in Paneth cells, improved Paneth cell architecture and gut barrier function at levels induced by chronic treatment, even 6 months after rapamycin was withdrawn. Past rapamycin treatment also enhanced the regenerative potential of aged intestine in intestinal organoids. Full geroprotective effects of chronic rapamycin treatment can thus be obtained with a brief pulse of the drug.
Project description:Dynamic mRNA gene expression from the wildtype YSBN6 during a rapamycin treatment (rapamycin-induced downshift). Rapamycin was added to yeast cells growing exponentially on glutamine as sole nitrogen source. A sample was taken at steady-state 10 minutes before , and then 3, 7, 10, 14, 24, 56 and 120 minutes after rapamycin treatment. Biological triplicate gene expression was measured for samples -10, 7 and 24 minutes after shift, for a total of 14 chips. Changes were generally evaluated relative to the steady-state point (-10 minutes). Biological variability can be assessed from the replicates time points. Other dynamic omics data are associated with this dataset. Consult the publication for more details.
Project description:p73 is a p53 family transcription factor that plays critical roles during development and tumor suppression. We analyzed p73 activity using a combination of ChIP-on-Chip and gene expression profiling, both at baseline and after treatment with the mTOR inhibitor rapamycin. This SuperSeries is composed of the SubSeries listed below.
Project description:RNA sequencing of mouse liver and kidney. UMHET pups were treated with diet containing encapsulated rapamycin or encapsulating material as a control from birth to 45 days of age, and tissues were collected at 2, 20-22 and 27-29 months of age from both males and females, and 3-5 samples per age, sex and treatment were sequenced.
Project description:Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process of effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Results: Colony formation and sulforhodamine B (IC50 < 1nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI was significantly associated with tumor size or lymph node status. High (>75) percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.01) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In Wang dataset, RMI predicted time to disease relapse (P = 0.09). Conclusions: Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment. Mol Cancer. 2009 Sep 24;8(1):75.
Project description:Compound CID 3538206 inhibits yeast TORC1 activity and functionally mimic rapamycin. We used microarrays to compare the global gene expression with the treatment of CID 3528206 and rapamycin. BY4741 yeast cells were treated with1% DMSO, 20 uM CID 3528206 and 200 nM rapamycin in duplicate for 3hrs. RNA extracted and labeled to probe yeast gene arrays