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1 Molecular Pharmacology & Toxicology, University of Southern California School of Pharmacy, Los Angeles, CA, USA
2 Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, USA
3 Molecular Pharmacology & Toxicology, University of Southern California School of Pharmacy, Los Angeles, CA, USA; Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA, USA
4 Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, MD, USA
5 Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, USA; Division of Surgical, Therapeutics, and Bioengineering Sciences, University of Southern California School of Dentistry, Los Angeles, CA, USA
6 Molecular Pharmacology & Toxicology, University of Southern California School of Pharmacy, Los Angeles, CA, USA; Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: ann{at}usc.edu.
We recently showed that Etk/Bmx, a member of the Tec family of non-receptor tyrosine protein kinases, promotes tight junction formation during chronic hypoxic exposure and augments normoxic VEGF expression via a feedforward mechanism. In this study, we further characterized the role of Etk in potentiating hypoxia-induced gene expression in salivary epithelial Pa-4 cells. Using transient transfection in conditionally activated Etk (i.e., 
Etk:ER) cells, we demonstrated that Etk enhances hypoxia-response element (HRE)-dependent reporter activation in both nonhypoxic and hypoxic conditions. This Etk driven reporter activation is ameliorated by the treatment of either Wortmannin or LFM-A13. Furthermore, by employing lentiviral-mediated gene delivery and siRNA technology, we provided direct evidence that hypoxia leads to a transient activation of both Etk and Akt, and that the activation of hypoxia-mediated Akt activation is Etk-dependent. Northern analyses confirmed that Etk activation led to the induction of steady-state mRNA levels of endogenous VEGF and PAI-1, a hallmark of hypoxia-mediated gene regulation. We also demonstrated that Etk utilizes a PI3-K/Akt pathway to promote reporter activation driven by NF-
B, another oxygen-sensitive transcription factor, and to augment cytokine-induced iNOS expression in endothelial cells. In order to establish the clinical relevance of Etk-induced, hypoxia-mediated gene regulation, we next examined the Etk expression in keloid, a skin fibrotic model which harbors elevated level of VEGF and PAI-1. We found that Etk is overexpressed in keloid (but not in normal skin) tissues. The differential steady-state levels of Etk protein were further confirmed in primary cultures of fibroblasts derived from these tissues, suggesting a role of Etk in tissue fibrosis. Taken together, our results provide a further understanding of how Etk functions within multiple signaling cascades to govern adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial, brain endothelial cells, and dermal fibroblasts
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