Cellular and biochemical studies of the glutaminase enzyme and its relation with cancer

Abstract

An emerging area in cancer biology is pointing to the fact that the already characterized genes responsible for the control of the growing process, cellular division, adhesion, metastasis and programmed cell death are also involved on the metabolism control. Cell proliferation requires nutrients, energy, and biosynthetic activity to duplicate all macromolecular components during each passage through the cell cycle. Therefore, while the metabolism of quiescent cells focus on oxidative phosphorilation, tumor cells present highly activated glycolytic pathway on the presence of oxygen (Warburg effect), de novo lipids biosynthesis and anaplerose dependent on glutamine. Tumor cells consume gutamine at unusual high rates, and its metabolism, called glutaminolysis, seems to be essential for the neoplastic transformation since its inhibition decreases cell proliferation. The transcription factors myc, HIF-1 and the PI3K/AKT/mTOR signaling pathway have been involved on the superactivation of the glicolytic pathway enzymes and on the truncation of the tricarboxilic acid cycle (TCA). However very little is known regarding how signaling pathways and transcription activators can promote the glutaminase activation in cells. It is on this plataform that this project proposes the study of the functional importance of the different isoforms of glutaminase, the biochemical and structural characterization of its potential binding partners and the understanding of how internal signaling can promote its activation.An emerging area in cancer biology is pointing to the fact that the already characterized genes responsible for the control of the growing process, cellular division, adhesion, metastasis and programmed cell death are also involved on the metabolism control. Cell proliferation requires nutrients, energy, and biosynthetic activity to duplicate all macromolecular components during each passage through the cell cycle. Therefore, while the metabolism of quiescent cells focus on oxidative phosphorilation, tumor cells present highly activated glycolytic pathway on the presence of oxygen (Warburg effect), de novo lipids biosynthesis and anaplerose dependent on glutamine. Tumor cells consume gutamine at unusual high rates, and its metabolism, called glutaminolysis, seems to be essential for the neoplastic transformation since its inhibition decreases cell proliferation. The transcription factors myc, HIF-1 and the PI3K/AKT/mTOR signaling pathway have been involved on the superactivation of the glicolytic pathway enzymes and on the truncation of the tricarboxilic acid cycle (TCA). However very little is known regarding how signaling pathways and transcription activators can promote the glutaminase activation in cells. It is on this plataform that this project proposes the study of the functional importance of the different isoforms of glutaminase, the biochemical and structural characterization of its potential binding partners and the understanding of how internal signaling can promote its activation. (AU)