Mechanisms linking nutrient supply &cell cycle/survival

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Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
 
Project Description:
Nutrient availability affects cell growth, proliferation and survival. Apart from pancreatic beta cells, skeletal myocytes, adipocytes and hepatocytes, there is a dearth of information about how cells respond to positive energy balance in the whole animal. Using endothelial cells as a prototypic cell lineage that is resistant to transformation, we will characterize cellular responses to the availability of a nutrient source, glucose, in excess of metabolic requirements (relevant to Projects 2, 3). High concentrations of external glucose trigger an autoregulatory mechanism to limit both glucose uptake and growth factor signaling, while stimulating intracellular pathways that regulate cell proliferation and apoptosis (examined in Project 2). Specifically, we have found that incubation of primary endothelial cells in 25 mM glucose induces c-myc transcription, activation of NF-kB pro-inflammatory pathways and downregulation of PI3-K/Akt signaling (relevant to Projects 2,4) in this cell type. These findings extend a growing appreciation that oncogenes, tumor suppressor genes, and signal transduction pathways are tightly coupled to changes in nutrient availability and energy metabolism. Having established how proliferative responses are coupled to nutrient excess in cells that resist transformation, we will investigate how primary mammary epithelial cells respond to excess glucose availability/We hypothesize that cells that are susceptible to neoplastic transformation will exhibit distinct identifiable responses to nutrient excess that favor cell proliferation. Finally, we will determine whether immortalized, initiated mammary epithelial cells exhibit heightened sensitivity to the effects of glucose excess, providing an epigenetic mechanism for tumor promotion. This project addresses key questions for obesity and cancer risk: how nutrient excess is coupled to changes in cell proliferation and survival, and at which point in carcinogenic progression does energy balance become critical. Insights gained from these investigations will provide novel frameworks for analyzing the effects of obesity on site-specific cancers in animal models and human populations (relevant to Projects 2-5).
 
Project Terms:
address adipocytes affect animal model animals apoptosis c-myc genes cancer prevention cancer risk cell cycle cell growth cell lineage cell proliferation cell type cells coupled down-regulation endothelial cells energy balance energy metabolism epigenetic process epithelial cells exhibits glucose glucose uptake growth factor hepatocyte human inflammatory insight investigation link malignant neoplasms mammary gland mediating metabolic metabolism modeling muscle fibers neoplastic cell transformation nf-kappa b novel nutrient obesity pathway interactions population resistance response signal transduction signal transduction pathway site source structure of beta cell of islet suppressor genes testing transcriptional activation tumor promoters tumor promotion tumor suppressor genes nutrition prevention cancer genetics
Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
Organization: Fred Hutchinson Cancer Research Center, United States, Washington, SEATTLE
Principal Investigators (PI): Hockenbery David Mark, US
 
Project Categories:
Natural Sciences > Aging Diseases and Pathology > Cancer & related diseases > Malignant neoplasms (including in situ)
 
Other Information:
Fiscal Year: 2009
Project Start Date: 1 September 2009
Project End Date: 31 August 2010
Project program: Specialized Center--Cooperative Agreements
 
Project Funding Information:
Funding Mechanism: Research Centers
Year Funding Organization Total Funding, $
2009 NIH - National Cancer Institute $362,299
Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
 
Title FY Funding
There are no results for this project in database.
Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
 
Project Title Organization FY Funding
Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
 
Title Journal Year Country Rel
Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
 
Title Year
Project Title: Mechanisms linking nutrient supply &cell cycle/survival
Project Number: 5U54CA116847-05-0001
Project web address: Follow on NIH
Parent Project: 5U54CA116847-05
 
Title Phase Year