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Structural relationships of the flavonoid apigenin and hnRNPA2 define the role of plant phytochemicals in the regulation of alternative splicing

Grant number: 13/50362-6
Support Opportunities:Regular Research Grants
Duration: October 01, 2013 - September 30, 2014
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Convênio/Acordo: Ohio State University
Principal Investigator:Roberto Kopke Salinas
Grantee:Roberto Kopke Salinas
Principal researcher abroad: Andrea I. Doseff
Institution abroad: Ohio State University, Columbus, United States
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:11/07777-5 - Cyclic di-GMP signaling and the Type IV macromolecule secretion system in Xanthomonas citri, AP.TEM


Flavonoids are emerging as potential dietary anti-carcinogenic and anti-inflammatory compounds as illustrated in vitro in several systems and in vivo in animal models1. Yet, their mechanisms of action remain poorly characterized. Recently, we describe the identification of human cellular targets of apigenin, a flavonoid abundantly present in fruits and vegetables. We found that apigenin binds to the Heterogeneous Nuclear RiboNucleoProtein A2 (hnRNPA2), a protein involved in splicing regulation, mRNA stability, and mRNA transport2. In addition, high leveis of HnRNPA2 have been associated with carcinogenesis and hnRNPA2 is a cellular markerfor cancer progression3-6. Our studies showed that apigenin alters the splicing isoforms present in cancer cells making them to resemble non-carcinogeneic cells (Arango et al, 2013. PNAS). In addition, we found that apigenin binds to the C- terminal Glycine Rich Domain (GRD) of hnRNPA2, preventing hnRNPA2 from forming homodimers, but has no interactions with the N-terminal RNA binding domain. Previous studies showed that homodimer formation is necessary for the binding of hnRNPA2 to RNA7. However, what is lacking is the understanding on how apigenin regulates hnRNPA2 structurally, altering its function. In order to answer this question we propose to use high- resolution Nuclear Magnetic Resonance (NMR) spectroscopy in order to evaluate how apigenin recognizes hnRNPA2 at the atomic level. (AU)

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