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Investigation of the molecular mechanisms involved in G2- mitosis transition blockage induced by FGF2 in Ras-driven malignant cells

Grant number: 13/09040-5
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2013
Effective date (End): April 30, 2017
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Hugo Aguirre Armelin
Grantee:Cecilia Sella Fonseca
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


The interest of our laboratory is the understanding of the mechanisms regulating the cell cycle of eukaryotes. Disarrangements in these mechanisms may sentence cells to death or, at the opposite extreme, cause malignant transformation, and therefore are involved in the etiology of cancers and other important diseases. In 2008, we published that FGF2, a classic growth factor with several pro-tumor activities, has an antiproliferative effect selectively in cells transformed by Ras. Since then we seek to understand this phenomenon and found that FGF2 prevents cells from entering mitosis. The treatment during the first four hours of the division cycle is sufficient to block the cells in G2 and, if the treatment is maintained in a sustained manner, we observe apoptotic death 48 hours after addition of FGF2 to the culture medium. The discovery of the inhibition of G2-mitosis transition is recent, and despite the progress made, we do not understand this blockade molecularly. Furthermore, in our laboratory were selected sub-lines resistant to this toxic effect of FGF2. These cells were able to overcome the blockade in G2, and my undergraduate research data indicate that this overcome and the emergence of the resistant phenotype depends on the elimination of one of the markers chromosomes of the cell lineage that we use. This chromosome carries about half of the amplified copies of K-Ras . The other half of the copies is carried by the second marker chromosome, and preliminary data indicate that its elimination in resistant strains did not occur possibly due to the fact that this chromosome is the only one in these cells that has active ribosomal genes. The objective of this project is to understand how the treatment with FGF2 functionally disarranges the proteins that control the onset of mitosis, and leaves the cells blocked in G2. For this, we will investigate the activation state of key proteins that control this transition by western blot and in parallel, we will establish a protocol for quantitative fosfoproteomics to have a global view of this breakdown in cells treated with FGF2. In addition, we will use conventional cytogenetic techniques, such as banding and in situ hybridization to characterize karyotypic changes involved in overcoming the blockade induced by FGF2 and emergence of resistant phenotype. These approaches can allow us to identify the target proteins which are responsible for the toxic effect of FGF2, what will characterize molecularly a new and unexpected function of this growth factor. (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)
DIAS, MATHEUS H.; FONSECA, CECILIA S.; ZEIDLER, JULIANNA D.; ALBUQUERQUE, LAYRA L.; DA SILVA, MARCELO S.; CARARO-LOPES, EDUARDO; REIS, MARCELO S.; NOEL, VINCENT; DOS SANTOS, EDMILSON O.; PRIOR, IAN A.; et al. Fibroblast Growth Factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors. MOLECULAR ONCOLOGY, v. 13, n. 2, p. 290-306, . (12/20186-9, 13/09040-5, 13/24212-7, 16/17945-6)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
FONSECA, Cecilia Sella. Molecular mechanisms of the cytotoxic effect of FGF2 in rastransformed cells. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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