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FGF2 dual function in cell cycle control: mitogen and tumor suppressor

Grant number: 08/51273-9
Support type:Research Projects - Thematic Grants
Duration: January 01, 2009 - December 31, 2013
Field of knowledge:Biological Sciences - Biochemistry
Principal researcher:Hugo Aguirre Armelin
Grantee:Hugo Aguirre Armelin
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


Recently we reported for the first time a dual action of FGF2 (Fibroblast Growth Factor 2) in ras-dependent malignant cells, triggering ERK-MAPK and PI3K mitogenic pathways and initiating a novel pathway mediated by FGFR-TyrKinase→RhoA-GTP, that blocks cell cycle and causes senescence. This antagonistic phenomenon sharply stands against the notion that FGF2 is oncogenic, suggesting that FGF2 might indeed initiate tumor suppressor mechanisms to inhibit malignant proliferation. In this proposal we will focus on a new general hypothesis for FGF2-dual action in cell cycle control, promoting the GO→G1→S transition and inhibiting G2→M. Inhibition of G2→M is reversible in normal cells, but, cytotoxic in malignant cells. Two complementary hypotheses are also included for test a) Cyclin D1 complements Ras oncogenic action and b) FGF2 cytotoxicity does not depend on pRb and p53 tumor suppressor pathways. For hypotheses testing we will use 2 cell lines of mouse and 2 of humans, transformed by K-ras or the chimera ER-rasV12, whose product is the hydroxi-tamoxifen-inducible ER-RasV12 fusion-protein. The complete approach will involve, by one side, mathematical modeling and computer simulation of cell cycle and, by the other, experimental analysis of cell cycle dynamics in a flow cytometer. The long term goal is a multi-scale resolution model that goes from molecular signaling pathways to cellular progression through cell cycle phases. In addition to functional pathways elucidation we also aim to uncover physical interactions between FGF2 isoforms of 18 and 22 kDa and FGFRs and/or intracellular proteins. (AU)

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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)
HATANAKA, ELAINE; DERMARGOS, ALEXANDRE; HIRATA, APARECIDA EMIKO; RAMIREZ VINOLO, MARCO AURELIO; CARPINELLI, ANGELO RAFAEL; NEWSHOLME, PHILIP; ARMELIN, HUGO AGUIRRE; CURI, RUI. Oleic, Linoleic and Linolenic Acids Increase ROS Production by Fibroblasts via NADPH Oxidase Activation. PLoS One, v. 8, n. 4 APR 8 2013. Web of Science Citations: 20.
FORTI, FABIO L.; ARMELIN, HUGO A. Arginine vasopressin controls p27(KiP1) protein expression by PKC activation and irreversibly inhibits the proliferation of K-Ras-dependent mouse Y1 adrenocortical malignant cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1813, n. 8, p. 1438-1445, AUG 2011. Web of Science Citations: 2.

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