Study of the molecular mechanism activation of Wnt/Beta Catenin Signaling pathway by Ouabain in rat hippocampus.

• Grant number: 11/22844-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2012
• End date: August 31, 2016
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Cristoforo Scavone
• Grantee: Ana Maria Marques Orellana
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 15/13295-4 - Ouabain as an antiapoptotic drug in neurodegenerative diseases., BE.EP.DR

Abstract

The Na +, K +-ATPase (Sodium Potassium Adenosine Trisfosfatase) is a highly conserved membrane protein in eukaryotes that establishes and maintains high intracellular concentrations of K+ and low Na+ through the hydrolysis of one ATP molecule. However, in addition to its regulatory role in ion homeostasis, studies suggest it's role in signal transduction and activation of gene transcription.In the presence of ouabain (OUA), an endogenous cardiotonic steroid, Na+, K+ - ATPase is able to promote intracellular Ca2+ levels oscillation and turn on the Src signaling pathway, with transactivation of the epidermal growth factor receptor (EGFR), and the MAPK signaling pathway (mitogen-activated protein kinase), which in turn can activate various transcription factors such as NF-kB (nuclear transcription factor kappa B). NFkB regulates the expression of genes that control programmed cell death, cell adhesion, proliferation, inflammation and tissue remodeling. Once activated, NFkB signaling pathway seems to modulate the activation of other signaling pathways, such as the canonical Wnt pathway (Wnt / Beta-catenin). Recently published data have shown that activation of EGF receptors may lead to transactivation of nuclear Beta-catenin, modulating the effector of the canonical Wnt pathway, without necessarily leading to activation of this pathway through its Frizzled receptor. Previous data from our laboratory showed that after 1 hour of OUA infusion, the NFkappaB signaling pathway is active, after 10 hours it can be seen an increase in phosphorylation ratio of GSK-3Beta protein, and after 24 hours there was an increase in nuclear translocation of Wnt/Beta-catenin. Thus, this project aims to determine the molecular mechanism of this modulation, since these pathways are intimately associated with the onset of neurodegenerative diseases, cancer and inflammatory processes.

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)

ORELLANA, ANA MARIA; LEITE, JACQUELINE ALVES; KINOSHITA, PAULA FERNANDA; VASCONCELOS, ANDREA RODRIGUES; ANDREOTTA, DIANA ZUKAS; LIMA, LARISSA DE SA; XAVIER, GILBERTO FERNANDO; KAWAMOTO, ELISA MITIKO; SCAVONE, CRISTOFORO. Ouabain increases neuronal branching in hippocampus and improves spatial memory. Neuropharmacology, v. 140, p. 260-274, SEP 15 2018. (16/07427-8, 11/22844-0)

KINOSHITA, PAULA F.; YSHII, LIDIA M.; ORELLANA, ANA MARIA M.; PAIXAO, AMANDA G.; VASCONCELOS, ANDREA R.; LIMA, LARISSA DE SA; KAWAMOTO, ELISA M.; SCAVONE, CRISTOFORO. Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells. SCIENTIFIC REPORTS, v. 7, JUL 7 2017. (11/22844-0, 11/10303-5, 14/05026-0, 16/07376-4, 11/21308-8, 11/12255-8, 11/04327-9)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ORELLANA, Ana Maria Marques. Effects of Ouabain intrahippocampal injection in modulation of NFκB, BDNF/CREB and WNT-β-CATENIN signaling pathways in a time course of 24 hours.. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.