Gli Transcriptional Activity Is Essential for Kras-Induced Pancreatic Tumorigenesis and Regulates IKBKE/NF-\(\kappa\)B Activity in the Tumor Epithelium

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Gli Transcriptional Activity Is Essential for Kras-Induced Pancreatic Tumorigenesis and Regulates IKBKE/NF-\(\kappa\)B Activity in the Tumor Epithelium

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Title: Gli Transcriptional Activity Is Essential for Kras-Induced Pancreatic Tumorigenesis and Regulates IKBKE/NF-\(\kappa\)B Activity in the Tumor Epithelium
Author: Rajurkar, Mihir; de Jesus-Monge, Wilfredo E.; Driscoll, David R.; Appleman, Victoria A.; Huang, He; Cotton, Jennifer; Klimstra, David; Zhu, Lihua; Simin, Karl; Xu, Lan; McMahon, Andrew P.; Lewis, Brian; Mao, Junhao

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Citation: Rajurkar, Mihir, Wilfredo E. de Jesus-Monge, David R. Driscoll, Victoria A. Appleman, He Huang, Jennifer L. Cotton. Forthcoming. Gli transcriptional activity is essential for Kras-induced pancreatic tumorigenesis and regulates IKBKE/NF-\(\kappa\)B activity in the tumor epithelium. Proceedings of the National Academy of Science.
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Abstract: Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignances, is thought to be initiated by KRAS activation. Here we find that transcriptional activation mediated by the Gli family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture, and Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 activation in the mouse pancreas accelerates Kras-driven tumor formation, underscoring the importance of Gli transcription factors in pancreatic tumorigenesis. Interestingly, we demonstrate Gli-stimulated IKBKE (IKK\(\varepsilon\))/nuclear factor-\(\kappa\)B (NF-\(\kappa\)B) activity in pancreatic cancer cells in culture and in vivo, and show that this activity is a critical downstream mediator for Gli-dependent PDAC cell transformation and survival. Together, these studies demonstrate for the first time the requirement for Gli in Kras- dependent pancreatic epithelial transformation, implicate a novel mechanism of Gli-NF-\(\kappa\)B oncogenic activation, and provide genetic evidence supporting the therapeutic targeting of Gli activity in pancreatic cancer.
Terms of Use: This article is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAP
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:8531456

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  • FAS Scholarly Articles [6463]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
 
 

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