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Two cell cycle regulatroy protein families: from functional studies to their use as novel diagnostic markers and therapeutic targets in cancer

Abstract

Cancer is among the diseases that most kill humans and domestic animals. Depending on the tissue and cell type affected by mutations, a large number of subtypes of cancer can be differentiated. For a specific subtype of cancer the molecular causes can be quite heterogeneous and for the majority of cases are poorly mapped. This represents both a major challenge as well as an an opportunity in the field, since an intense study of the molecular causes can lead to new diagnostic and therapeutic strategies. Protein kinases in signaling pathways and regulatory proteins in general, are frequently affected by activating or inactivating mutations in cancer and therefore contribute to cancer transformation. In this project we focus on two families of proteins with great potential of utility for both diagnostic and therapy in cancer. The first family is represented by the less studied members Nek1,4,6,8, 10 e 11, which are involved in the regulation of the cell cycle, mitosis, primary cilia function, DNA repair mechanisms and mitochondrial functions. The second family comprises the two human regulatory proteins, called HABP4 and SERBP1, that have roles in the regulation of transcription and gene expression, cell proliferation and the cells responses to stress. The central aim of this project is the study of the molecular functions of these proteins in the cell and the characterization of the effect of point mutations in their genes found in human cancers. Using immune-histochemistry and transcriptome analysis we will characterize these proteins expression profile in cancer cells and the expression and regulation of mRNAs. This approach will allow us to identify for which cancer types each of the proteins studies serves as a molecular diagnostic marker and will also suggest new roads of therapeutical intervention. We will generate cell lines with gene knock out (Crispr Cas 9) and overexpression for these proteins, for 2D and 3D, cell culture models. Structural modeling and biochemical assays will allow the discovery and development of new inhibitors for the Nek protein kinases, providing new chemical probes for cancer treatment studies. (AU)

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