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

Grant number: 09/10875-9
Support type:Research Grants - Young Investigators Grants
Duration: February 01, 2010 - October 31, 2014
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Sandra Martha Gomes Dias
Grantee:Sandra Martha Gomes Dias
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Assoc. researchers:Andre Luis Berteli Ambrosio
Associated scholarship(s):14/17820-3 - Post-transcriptional regulation of glutaminase enzyme by HuR and its relationship with high glutaminolytic levels in tumors, BP.DD
14/06512-6 - Epigenetic study of histone demethylases enzymes Fe (II) and ±-ketoglutarate dependent of the jumonji family in the context of tumoral metabolism and glutaminase activity, BP.DD
13/23510-4 - Understanding how PI3K/Akt/mTOR and AMPK signaling pathways affect glutaminase activity, BP.DR
+ associated scholarships 13/12186-1 - Search for alternative anaplerotic sources of the TCA as new targets against triple-negative breast cancer, BP.MS
12/16881-3 - Study of the GAC and KGA mRNA and protein expression levels, BP.MS
12/09452-9 - Transcriptome and metabolomic studies of cancer cells as a tool for understanding the metabolic adaptation process, BP.DD
12/11577-4 - Studies of the metabolic alterations related to the PI3K-Akt pathway and ras oncogene co-activation, BP.PD
11/21863-1 - Identification of glutaminase interacting partners and functional studies, BP.PD
11/13981-4 - Understanding the cell signalization pathways that impact on glutaminase activity, BP.MS
11/09512-9 - In vitro and in vivo studies of the Glutaminase C and Kidney-Type Glutaminase importance for the cancer metabolism, BP.PD
11/10127-2 - Studies of the nuclear location and nuclear receptor interaction of glutaminases, BP.DR
11/06654-7 - Screening of natural extracts for glycolytic and glutaminolytic inhibitory properties as a platform for searching new anti-tumours compounds, BP.PD
10/13992-3 - Biochemical and cellular characterization of the Kidney-Type Glutaminase in complex with its partners, BP.MS
10/05987-0 - Structural determination of the kidney type glutaminase and the search for its binding partners, BP.PD
09/18260-3 - Cellular and biochemical studies of the glutaminase and its relation with cancer, BP.JP - associated scholarships

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)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SCOTA FERREIRA, AMANDA PETRINA; CASSAGO, ALEXANDRE; GONCALVES, KALIANDRA DE ALMEIDA; DIAS, MARILIA MEIRA; ADAMOSKI, DOUGLAS; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; HONORATO, RODRIGO VARGAS; DE OLIVEIRA, JULIANA FERREIRA; FERREIRA, IGOR MONTEZE; FORNEZARI, CAMILA; BETTINI, JEFFERSON; LOPES OLIVEIRA, PAULO SERGIO; PAES LEME, ADRIANA FRANCO; PORTUGAL, RODRIGO VILLARES; BERTELI AMBROSIO, ANDRE LUIS; GOMES DIAS, SANDRA MARTHA. Active Glutaminase C Self-assembles into a Supratetrameric Oligomer That Can Be Disrupted by an Allosteric Inhibitor. Journal of Biological Chemistry, v. 288, n. 39, p. 28009-28020, SEP 27 2013. Web of Science Citations: 30.
CASSAGO, ALEXANDRE; FERREIRA, AMANDA P. S.; FERREIRA, IGOR M.; FORNEZARI, CAMILA; GOMES, EMERSON R. M.; GREENE, KAI SU; PEREIRA, HUMBERTO M.; GARRATT, RICHARD C.; DIAS, SANDRA M. G.; AMBROSIO, ANDRE L. B. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 109, n. 4, p. 1092-1097, JAN 24 2012. Web of Science Citations: 108.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.