Mechanisms associated with loss of regulation of NADPH oxidase Nox1 by protein disulfide isomerase in cells with sustained activation of the Ras pathway

• Grant number: 13/02070-6
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): September 01, 2013
• Effective date (End): December 31, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Tiphany Coralie de Bessa
• Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated scholarship(s): 16/00686-8 - Mechanisms underlying the loss of protein disulfide isomerase-dependent regulation of NADPH oxidase in colon carcinoma cells with Ras overactivation, BE.EP.DR

Abstract

Understanding the mechanisms whereby the endoplasmic reticulum chaperone PDI (protein disulfide isomerase) converges with Nox NADPH oxidase enzymatic complex(es) is the central goal of our Thematic Project. In this direction, the observation that in tumor cells with high constitutive Nox1 expression and a K-Ras mutation there occurs a deregulation of PDI-Nox1 interaction indicates an interesting model to be explored, since in vascular smooth muscle cells a physical and functional convergence between Nox1 and PDI has been consistently tested and observed in our group. The central question of the present project is whether the presence of activated Ras can be a determinant factor of Nox1 deregulation by PDI via interference with otherwise normal pathways of RhoGTPase regulation by PDI. Our main goal is elucidate a functional model of Nox regulation by PDI through comparative analysis or tumor and vascular cells submitted or not to cell stresses, as well as with distinct tumorigenic phenotypes or adaptive responses. Specific goals: 1) To investigate the functional interaction between PDI and Nox1 in tumor cells expressing or not mutated Ras, through PDI loss- or gain-of-function experiments; 2) To obtain and to validate a model of vascular smooth muscle cells displaying activated Ras, in which functional interaction between PDI and Nox1 will be investigated through PDI loss- or gain-of-function experiments; 3) To investigate mechanisms whereby the tumoral state and/or Ras mutation affect Nox regulation by PDI, with a particular focus on small RhoGTPases (Rac1, RhoA and Cdc42); 4) T investigate the functional implications of Ras and RhoGTPase-related pathways with respect to cell migration. Understading the mode of interaction between PDI and small GTPases is likely to have important implications in (patho)physiology. (AU)

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)

DE BESSA, TIPHANY CORALIE; PAGANO, ALESSANDRA; SOARES MORETTI, ANA IOCHABEL; SANTOS OLIVEIRA, PERCILLIA VICTORIA; MENDONCA, SAMIR ANDRADE; KOVACIC, HERVE; MARTINS LAURINDO, FRANCISCO RAFAEL. Subverted regulation of Nox1 NADPH oxidase-dependent oxidant generation by protein disulfide isomerase A1 in colon carcinoma cells with overactivated KRas. CELL DEATH & DISEASE, v. 10, FEB 13 2019. Web of Science Citations: 2.