Metabolic Analysis of the Effects of High Expression Levels of Bcl-2/xL Protooncogenes on Carbohydrate Metabolism.

摘要

The Bcl-2 proto-oncogene expression plays an essential role in the regulation of mitochondrial function and fuel metabolism. Mitochondrial enzymes and anti-apoptotic proteins can participate to cross-regulation processes between the programmed cell death and cell metabolism.;An NMR-based metabolomics approach was used to answer how the pro-oncogenes' Bcl-xL or Bcl-2 levels affect carbohydrate metabolism. Also, to define if the metabolic regulations associated with Bcl-2/xL up-regulations are connected to their intrinsic cell death regulatory function.;Metabolite pools modulated by Bcl-2 family members were measured by NMR. The cellular pools of two main metabolites (e.g. fumarate and pyruvate), were shown as to be differentially affected in Bcl-2/xL over-expressions genetic context. These metabolites are associated with a variety of pathways involved in glucose fuel metabolism such as: the TCA cycle, pyruvate metabolism, glycolysis, and gluconeogenesis. These metabolic pathways link apoptosis to cell metabolism in a cancer context through the Bcl-2 protein family. This implies that these over-expressions affect a number of intermediate metabolites in several metabolic pathways.;This thesis examined the cross-signaling processes between apoptosis and metabolism. Members of the Bcl-2 family proteins are implicated in the regulation of carbohydrate metabolism, indicating that pathways involved in metabolism and apoptosis are linked. Therefore, several core apoptotic proteins eventually allow for the regulation of metabolism and cell death.