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Molecular attack in the control of cell proliferation and neoplasms

Abstract

Normal cell proliferation is controlled by extracellular regulators (classic peptidic and steroidic hormones)and peptidic growth factors. Two main types of genic products participate in the cell response to these extracellular regulators, the products of oncogenes and of tumor suppressant genes. Alterations in these products lead to the appearance of tumors (neoplasms). The General Objective of this project is to clarify the molecular bases of the phenomenon of (tumoral-normal) phenotypical reversion induced by glucocorticoid hormones in C6/STl mice glioma cells and of the malignant transformation caused by the "middle T” (MT) oncogene of polyomavirus in 3T3 mouse cells. Three specific objectives are proposed: 1. analysis of the genes regulated by glucorticoids in C6/STl cells, by molecular cloning, using differential hybridization, "differential display of RNA", among other techniques; structural and functional characterization of the isolated cDNAs and test of the role of their genic products in phenotypic reversal by interference (use of anti-sense oligonucleotide in C6/8Tl cells) and super-expression (in the C6/P7 cells that do not suffer phenotypic reversion). Analysis of the expression of oncogenes and tumor suppressant genes, at the level of RNA and/or protein using specific probes and antiserums. 2. analysis of the molecular alterations provoked by MT of polyomavirus, particularly in the expression of the genes of primary response to peptidic growth factors (proto-oncogenes c-fos, c-jun, c-myc, c-rei; interleukin JE, KC) and of the interaction of MT with cell proteins involved in the proliferative signal transduction. 3. production of recombinant oncoproteins (members of the Fos and Jun families, suppressor of RB tumor, products of genes regulated by glucocorticoids) in vectors of expression of prokaryotes (bacteria) and eukaryotes (baculovirus/insect cells) for the generation of specific anti-serums. It is hoped to be able to contribute to broaden knowledge on the molecular bases of malignant transformation induced by tumoral viruses and of the anti-tumor effect of glucocorticoid hormones. The molecular focus adopted could generate new insights in the design of drugs to suppress cell division that could be used in tumor therapy. (AU)

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