Yanira Figueroa Department of Pharmacology Tulane University 1430 Tulane Avenue New Orleans, Louisiana 70112 ygutier@tulane.edu I am interested in understanding the mechanism(s) of signal transduction activated in Hep3B carcinoma cells during hypoxia. Derangements of oxygen tension caused by decreased tissue perfusion or increased oxygen consumption, commonly found in a variety of diseases like cancer and arteriosclerosis, will activate different mechanisms to help cells adapt and survive in the new environment. Diverse genes like endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and erythropoietin (EPO) are upregulated in response to hypoxia by a common transcription factor named Hypoxia Inducible Factor -1 (HIF-1). HIF-1 was identified as a heterodimeric transcription factor composed of two different subunits; alpha and beta. The alpha subunit is induced by hypoxia and quickly degraded by proteosomal ubiquitination in normoxia; and the beta subunit is constitutive. During hypoxia both subunits dimerize and translocate to the nucleus where they bind specific DNA sequences termed hypoxia-responsive elements (HRE). My research project is particularly interested in the survival signaling pathways that will lead to activation of HIF-1 and ultimately upregulation of erythropoiedin in Hep3B cells. There are two HREs in the 3' untranslated region of the EPO gene. We are dissecting first HIF-1 activation and subsequently EPO production in Hep3B cells with the use of selective pharmacological inhibitors of the PI3K, MEK and p38 signaling pathways as well as mutant and constitutive active genetic constructs. Our data have demonstrated the clear involvement of the phosphatidylinositol 3-kinase pathway in HIF-1 transcriptional activation and EPO protein expression. However, MEK or p38 activation activation was not observed during hypoxia and EPO production was not significantly affected. In addition, we have elucidated the importance of the transcription factor, nuclear factor kappa B (NF-kB) in HIF-1 mRNA gene expression. By inhibiting NF-kB with by transiently transfecting a dominant negative construct of IKB. HIF-1 as well as EPO gene expression were decreased. In summary, our lab is delineating the importance of the PI3K/AKT/NF-kB signaling pathway and its key role in HIF-1/EPO gene activation.     AKT Regulation of MAPK Signaling Pathway Provides a Potential Cross-Talk Mechanism for HIF-1 Gene Expression in Hep3B Cells Figueroa YG., Scanduro AB., Tang Y., and Beckman BS. download a PDF file of this poster   NF-kB Plays a Key Role in Hypoxia-Inducible Factor-1-Regulated Erythropoietin Gene Expression Yanira G. Figueroa, Anna K. Chan, Ranira Ibrahim, Yan Tang, Matthew E. Burow, Jawed Alam, Aline B. Scandurro, Barbara S. Beckman download a PDF file of this paper   Yanira Figueroa's Resume download a PDF document of this Resume