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Involvement of KIAA0090 gene in UPR-ERAD responses, autophagy and apoptosis, and effects of its knock down on the proteome of melanoma cells and melanocytes

Grant number: 12/17890-6
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 01, 2013
Effective date (End): December 31, 2013
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Enilza Maria Espreafico
Grantee:Rodrigo Ribeiro da Silva
Supervisor abroad: John C. Christianson
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Ludwig Institute for Cancer Research, Oxford, England  
Associated to the scholarship:10/10799-8 - Study of the role of KIAA0090 gene in neoplastic transformation and maintenance of the malignant phenotype, BP.DR

Abstract

The endoplasmic reticulum (ER) has two built-in mechanisms for controlling the quality of proteins that are in transit through secretory via: unfolded protein response (UPR) and endoplasmic reticulum-associated degradation (ERAD). Christianson and colleagues (2011) reported the involvement of human KIAA0090 gene in the formation of endoplasmic reticulum membrane complex (mEMC), previously described in S. cerevisae. In fast growing tumors, hypoxia and oxidative stress may induce UPR / ERAD and these responses generate a protective effect on tumor cells, preventing them from being directed to apoptosis. Drugs that inhibit key molecules in UPR/ERAD pathways can prevent the adaptation of these cells in this tumor microenvironment, representing a new class of antitumor agents that must be further explored (Koong et al., 2006; Lee et al. 2,003 )Data presented in the submitted scientific report, showed that Kiaa0090 knockdown in B16-F10 murine melanoma cells diminishes cell proliferation, and the ability to generate tumors in animal models. We also observed a change in cell phenotype, with the generation of proliferative non-adherent cells, indicating some alteration in signaling pathways that may be involved in adhesion, migration, invasion and cell death.To gain evidence on the influence of Kiaa0090gene over these cellular functions and signaling pathways involved in them, and try to explain the observed phenotype, we intend to analyze global, cell surface and secreted fraction (superficioma and secretome) proteomes, as well as mitochondrial proteome in KIAA0090 knocked down melanoma cells and melanocytes. We will also evaluate the effect of Kiaa0090 knockdown in responses UPR / ERAD responses, and the connection apoptosis and autophagy.The internship abroad will be conducted under the supervision of John Christianson, first author of the paper that described the participation of Kiaa0090 in mEMC complex. The internship will be conducted at the Ludwig Institute for Cancer Research, linked to the University of Oxford, England (AU)