Nrf2 protein mediates HO-1 expression triggered by vGPCR

DAIANA SAPOCHNIK; PAULA RABINOVICH; MARTIN GARCIA SOLÁ; ENRIQUE MESRI; OMAR A. COSO

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Congreso; SISTAM 2012 - The Second South American Spring Symposium in Signal Transduction and Molecular Medicine? (SISTAM2012); 2012

50.- Nrf2 protein mediates HO-1 expression triggered by vGPCR Daiana Sapochnik1, Paula Rabinovich1, Martín García Solá1, Enrique Mesri2 & Omar Coso1 1Laboratorio de Fisiología y Biología Molecular. Facultad de Ciencias Exactas y Naturales, IFIBYNE UBA-CONICET, Buenos Aires, Argentina.. 2University of Miami School of Medicine Miami, USA. Heme oxygenase-1 (HO-1) is an enzyme upregulated by the Kaposi´s sarcoma-associated herpesvirus (KSHV) and highly expressed in human Kaposi Sarcoma (KS) lesions. The oncogenic G protein-coupled receptor (KSHV-GPCR or vGPCR) is expressed by the viral genome in infected cells and is involved in KS development, HO-1 expression and vascular endothelial growth factor (VEGF) expression. We have characterized that vGPCR induces HO-1 expression and HO-1 dependent transformation through the Ga13 subunit of heterotrimeric G proteins and the small GTPase RhoA. Narrowing down the molecular components that regulate vGPCR triggered HO-1 expression at the promoter level we found several lines of evidence that support a role for Nrf2 transcription factors and its associated family members as targets for vGPCR-Ga13-RhoA signaling. Cells expressing vGPCR show activation of different protein kinase pathways and our data indicates that the ERK2 and p38MAPK pathway act as intermediates in signaling from vGPCR to Nrf2. We found that the ERK2 MAPK pathway has an important role in Nrf2 translocation to the cell nucleus and in Nrf2 transactivation activity. Our current goal is to identify amongst the Nrf2 family members the actual protein target for MAPK dependent phosphorylation that leads to the increase observed in HO-1 expression in vGPCR expressing cells. Altogether, our studies show that vGPCR induces HO-1 expression through signaling pathways that target the HO-1 promoter via Nrf2 transcription factors, broadening the range of molecular potential therapeutic targets for KS or tumors with high HO-1 activity.