Nov 19, 2014

Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer

BioRxiv : the Preprint Server for Biology
Julien Y DutheilChristopher L Pin

Abstract

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+KrasLSL-G12D mice. In response to injury, KRASG12D bipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlike Ptf1acreERT/+KrasLSL-G12D mice, APK mice exhibited a cachexi...Continue Reading

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Mentioned in this Paper

Gene Polymorphism
Fracture, Incomplete
Patterns
Genome
Cranial Apex
Classical Lissencephaly
Gorilla <Eastern Gorilla>
Pan troglodytes
X Chromosome
Sorting - Cell Movement

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