The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis
Authors
Rajurkar, MihirDe Jesus-Monge, Wilfredo E.
Driscoll, David R.
Appleman, Victoria A.
Huang, He
Cotton, Jennifer L.
Klimstra, David S.
Zhu, Lihua Julie
Simin, Karl
Xu, Lan
McMahon, Andrew P.
Lewis, Brian C.
Mao, Junhao
UMass Chan Affiliations
Department of Cancer BiologyProgram in Molecular Medicine
Program in Gene Function and Expression
Document Type
Journal ArticlePublication Date
2012-04-24Keywords
AnimalsCarcinoma, Pancreatic Ductal
Cell Proliferation
*Genes, ras
I-kappa B Proteins
Mice
NF-kappa B
Pancreatic Neoplasms
Proto-Oncogene Proteins
Transcription Factors
Cancer Biology
Genetics and Genomics
Metadata
Show full item recordAbstract
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, 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 for 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-regulated I-kappa-B kinase epsilon (IKBKE) and NF-kappaB activity in pancreatic cancer cells and show that this activity is a critical downstream mediator for Gli-dependent PDAC cell transformation and survival. Together, these studies demonstrate the requirement for Gli in Kras-dependent pancreatic epithelial transformation, suggest a mechanism of Gli-NF-kappaB oncogenic activation, and provide genetic evidence supporting the therapeutic targeting of Gli activity in pancreatic cancer.Source
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):E1038-47. Epub 2012 Apr 9. Link to article on publisher's siteDOI
10.1073/pnas.1114168109Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43995PubMed ID
22493246Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1073/pnas.1114168109