Signaling pathways involved in cell transformation by virally encoded oncogenes. GPCRs, transcription factors and strategies for sustainable research in LMI countries.
CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
Kaposi’s sarcoma (KS) is the most common tumor in AIDS patients. The highly vascularized patient’s skin lesions are composed of cells derived from the endothelial/mesenchymal tissue transformed by the KSHV virus. The virus encodes a variety of genes being the expression of vGPCR, a constitutively active G Protein Coupled Receptor, a requisite for cell transformation. We have studied a major role for ERK/MAPK pathways as intermediates in signaling from vGPCR to HO-1 and COX-2 enzymes which inhibition attenuates cell transformation parameters. We observed that vGPCR induces target gene
expression both at the promoter level and by regulating mRNA stability. We have focused on the transcription factor Nrf2, with transactivation activity linked to HO-1 expression. Our data highlights the fundamental role of Nrf2 linking vGPCR signaling to the HO-1 promoter, acting upon HO-1 gene expression regulation and the tumorigenesis induced by vGPCR. We currently aim to develop a rational design of novel pharmacological stabilizers of complexes between Nrf2 and its natural inhibitor Keap1, oriented to increase Keap1-Nrf2 interface binding with a molecular “clip” mode of action as a new
strategy for therapeutic modulation of cell signaling in AIDS-related KS disease. Strategies for potentiating the outreach of our discoveries and resources in laboratories below the equator line will be discussed.