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dc.contributor.authorRajurkar, Mihir
dc.contributor.authorDe Jesus-Monge, Wilfredo E.
dc.contributor.authorDriscoll, David R.
dc.contributor.authorAppleman, Victoria A.
dc.contributor.authorHuang, He
dc.contributor.authorCotton, Jennifer L.
dc.contributor.authorKlimstra, David S.
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorSimin, Karl
dc.contributor.authorXu, Lan
dc.contributor.authorMcMahon, Andrew P.
dc.contributor.authorLewis, Brian C.
dc.contributor.authorMao, Junhao
dc.date2022-08-11T08:10:15.000
dc.date.accessioned2022-08-23T17:01:22Z
dc.date.available2022-08-23T17:01:22Z
dc.date.issued2012-04-24
dc.date.submitted2012-08-09
dc.identifier.citationProc Natl Acad Sci U S A. 2012 Apr 24;109(17):E1038-47. Epub 2012 Apr 9. <a href="http://dx.doi.org/10.1073/pnas.1114168109">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1114168109
dc.identifier.pmid22493246
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43995
dc.description.abstractPancreatic 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22493246&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1073/pnas.1114168109
dc.subjectAnimals
dc.subjectCarcinoma, Pancreatic Ductal
dc.subjectCell Proliferation
dc.subject*Genes, ras
dc.subjectI-kappa B Proteins
dc.subjectMice
dc.subjectNF-kappa B
dc.subjectPancreatic Neoplasms
dc.subjectProto-Oncogene Proteins
dc.subjectTranscription Factors
dc.subjectCancer Biology
dc.subjectGenetics and Genomics
dc.titleThe activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis
dc.typeArticle
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume109
dc.source.issue17
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pgfe_pp/203
dc.identifier.contextkey3194128
html.description.abstract<p>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.</p>
dc.identifier.submissionpathpgfe_pp/203
dc.contributor.departmentDepartment of Cancer Biology
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Gene Function and Expression
dc.source.pagesE1038-47


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