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Metabolic regulation of genetic and epigenetic control of gene expression

Abstract

Molecular mechanisms related to the tumorigenic process are traditionally related to oncogenes and tumor supressors deregulation, which control the signaling pathways responsible for the cell cycle regulation, cell growth, cell proliferation and cell death. On the other hand, new evidences point to an alternative mechanism where the primary role of the oncogenes and tumor supressors are to reprogram the cellular metabolism. This scenario is consistent with the recent discoveries that some metabolites can be oncogenic by itself, altering cell signaling and blocking cell differentiation. Such metabolic signals act by determining chromatin structure, since they are substrates for the enzymes involved on chromatin remodeling through histone and DNA modification. Changes on both actions will define epigenetic remodeling and genic transcriptional control. On this project, we will study how the glutamine metabolism into ±-ketoglutarate, specifically related to the glutaminases, affect chromatin remodeling and epigenetic control of pathways important for the cancer stem cell (CSC) phenotype maintenance. Although not very much appreciated, metabolic and nutrient signaling (either direct or intermediated by enzymes) also perform an important role on gene trancriptional control by altering the activity of several transcriptional factors. On this project, we will also evolve the findings made by our lab that the HIF (Hypoxia-inducible factor)-3± isoform directly interacts with lipids, by pursuing the understanding of how this interaction can affect this isoform activity; in addition, we want to describe the molecular and functional details of a protein-protein interaction discovered in our lab, involving the glutaminase and the nuclear receptor PPAR³. (AU)

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Scientific publications (7)
(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)
DIAS, MARILIA M.; ADAMOSKI, DOUGLAS; DOS REIS, LARISSA M.; ASCENCAO, CAROLLINE F. R.; DE OLIVEIRA, KRISHINA R. S.; PASCHOALINI MAFRA, ANA CAROLINA; DA SILVA BASTOS, ALLINY CRISTINY; QUINTERO, MELISSA; CASSAGO, CAROLINA DE G.; FERREIRA, IGOR M.; et al. GLS2 is protumorigenic in breast cancers. Oncogene, v. 39, n. 3, p. 690-702, . (13/05668-0, 14/18061-9, 12/14298-9, 13/23510-4, 14/17820-3, 14/06512-6, 14/15968-3, 15/25832-4, 12/09452-9, 14/20673-2, 16/06625-0, 12/11577-4, 11/10127-2)
DRAGOMIR, MIHNEA; MAFRA, ANA CAROLINA P.; DIAS, SANDRA M. G.; VASILESCU, CATALIN; CALIN, GEORGE A.. Using microRNA Networks to Understand Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 7, . (15/25832-4)
DE GUZZI CASSAGO, CAROLINA APARECIDA; DIAS, MARILIA MEIRA; PINHEIRO, MATHEUS PINTO; PASQUALI, CAMILA CRISTINA; SILVA BASTOS, ALLINY CRISTINY; ISLAM, ZEYAUL; CONSONNI, SILVIO ROBERTO; DE OLIVEIRA, JULIANA FERREIRA; GOMES, EMERSON MACHI; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; et al. Glutaminase Affects the Transcriptional Activity of Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) via Direct Interaction. BIOCHEMISTRY, v. 57, n. 44, p. 6293-6307, . (14/20673-2, 11/10127-2, 17/11766-5, 16/22246-0, 15/25832-4, 10/13992-3, 14/19518-2, 11/13981-4)
COSTA, RENNA K. E.; RODRIGUES, CAMILA T.; CAMPOS, JEAN C. H.; PARADELA, LUCIANA S.; DIAS, MARILIA M.; DA SILVA, BIANCA NOVAES; DE VALEGA NEGRAO, CYRO VON ZUBEN; GONCALVES, KALIANDRA DE ALMEIDA; ASCENCAO, CAROLLINE F. R.; ADAMOSKI, DOUGLAS; et al. High-Throughput Screening Reveals New Glutaminase Inhibitor Molecules. ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, v. 4, n. 6, p. 1849-1866, . (13/23510-4, 15/25832-4, 16/09077-4, 13/07600-3, 19/16351-3, 14/17820-3, 14/15968-3)
DOS REIS, LARISSA MENEZES; ADAMOSKI, DOUGLAS; OLIVEIRA SOUZA, RODOLPHO ORNITZ; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; CORREA-DA-SILVA, FELIPE; DE SA PATRONI, FABIO MALTA; DIAS, MARILIA MEIRA; CONSONNI, SILVIO ROBERTO; MENDES DE MORAES-VIEIRA, PEDRO MANOEL; et al. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. Journal of Biological Chemistry, v. 294, n. 24, p. 9342-9357, . (15/26059-7, 14/17820-3, 14/18061-9, 15/15626-8, 15/25832-4, 14/15968-3, 17/06225-5, 14/06512-6, 16/06034-2, 13/23510-4)
QUINTERO, MELISSA; ADAMOSKI, DOUGLAS; DOS REIS, LARISSA MENEZES; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; GONCALVES, KALIANDRA DE ALMEIDA; DIAS, MARILIA MEIRA; CARAZZOLLE, MARCELO FALSARELLA; GOMES DIAS, SANDRA MARTHA. Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer. BMC CANCER, v. 17, . (09/53853-5, 14/17820-3, 14/18061-9, 15/25832-4, 14/15968-3, 12/09452-9, 13/23510-4, 14/06512-6, 12/11577-4)
KRISHNA NAGAMPALLI, RAGHAVENDRA SASHI; NECIOSUP QUESNAY, JOSE EDWIN; ADAMOSKI, DOUGLAS; ISLAM, ZEYAUL; BIRCH, JAMES; SEBINELLI, HEITOR GOBBI; BRUNO MOREIRA GIRARD, RICHARD MARCEL; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; FALA, ANGELA MARIA; PAULETTI, BIANCA ALVES; et al. Human mitochondrial pyruvate carrier 2 as an autonomous membrane transporter. SCIENTIFIC REPORTS, v. 8, . (17/02391-8, 14/20673-2, 16/06034-2, 15/02734-7, 15/25832-4, 14/17820-3, 14/12663-7, 14/06954-9)

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