Analysis of metabolic responses to signals from the oncogene c-Myc a regulator of cell growth and proliferation.
EMSL Project ID
25606
Abstract
The ability of cells to grow, generate energy and respond to environmental stimuli is directly linked to cellular signaling mechanisms. Understand how these signal are regulated is an important question as dysregulation can lead to disease such as cancer and cardiac hypertrophy. In our work we use cell and mouse models to understand how a transcription factor and master regulator of cell growth, the c-myc oncogene (Myc), modifies cell metabolism to induce growth and proliferation. Myc is deregulated in 50% of human cancers and two decades of molecular research on this transcription factor have established Myc's role in regulation of genes required for cell proliferation and growth. While many Myc target genes have been identified it is still unclear how these genes cooperate to induce Myc's physiological effects. Metabolic pathways are prime examples of cooperative networks and metabolic genes are regulated by Myc but the significance of this regulation to cellular responses to Myc is poorly understood. In our funded NIH grant we proposed the use of Myc wild-type and null cell lines and mouse models with tissue specific, inducible Myc expression to address our hypothesis that Myc's regulation of metabolism contributes to Myc's induction of cell growth and proliferation. Briefly these models are being used to address two specific aims; Specific aim 1. Determine the metabolic changes that accompany Myc-induced cell proliferation and growth. Specific aim 2. Determine the metabolic changes arising during Myc-induced neoplasia in a mouse model of reversible pancreatic neoplasia. These studies come under the EMSL Science Theme of Biological Interactions, as this research would advance understanding of how oncogenes regulate metabolic networks. Our initial work with EMSL has demonstrated that Myc induces major changes in metabolism during serum induced cell cycle entry. 13C isotopomer analysis of cells grown in U-13C6 glucose demonstrate that Myc coordinately regulates the activation of glycolysis, pentose phosphate pathway, purine, pyrimidine metabolism and TCA cycle (see progress report). This ability to rapidly activate the assemble of essential resources for energy generation and production of metabolites for DNA and protein synthesis is a unique capability for a single molecule, and highlights the importance of these metabolic studies for our understanding of Myc function. To expand these studies to mouse models we are requesting access to EMSL facilities to perform 13C isotopomer analysis of Myc-induced growth in the heart and Myc-induced tumorogenesis in the pancreas. We anticipate breeding mice for these studies within the next six months and request access to EMSL facilities to begin NMR analysis. When completed these studies will provide distinct profiles of carbon metabolism linked to Myc induced neoplasia and growth. Recent research has revealed that targeting metabolic pathways may provide unique approaches to selectively kill cancer cells. Data generated from our 13C isotopomer and related metabolic studies will increase our knowledge of Myc's regulation of metabolic networks. While our interests are to further biomarker and drug discovery efforts for cancer diagnostics and treatment such results could also be applied to engineer metabolic pathways to increase growth and proliferation.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-10-15
End Date
2010-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry
F Morrish, N Isern, M Sadilek, M Jeffrey, and DM Hockenbery
Oncogene (2009) 28, 2485–2491 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 doi:10.1038/onc.2009.112
C NMR ISOTOPOMER ANALYSIS OF METABOLIC NETWORK REGULATION BY THE ONCOGENE C-MYC DURING CELL CYCLE ENTRY. Fionnuala Morrish-¹, Nancy Isern² and David Hockenbery¹