Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways

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Abstract

The tumor suppressor Lkb1/STK11/Par-4 is a key regulator of cellular energy, proliferation, and polarity, yet its mechanisms of action remain poorly defined. We generated mice harboring a mutant Lkb1 knockin allele that allows for rapid inhibition of Lkb1 kinase. Culturing embryonic tissues, we show that acute loss of kinase activity perturbs epithelial morphogenesis without affecting cell polarity. In pancreas, cystic structures developed rapidly after Lkb1 inhibition. In lung, inhibition resulted in cell-autonomous branching defects. Although the lung phenotype was rescued by an activator of the Lkb1 target adenosine monophosphate-activated kinase (AMPK), pancreatic cyst development was independent of AMPK signaling. Remarkably, the pancreatic phenotype evolved to resemble precancerous lesions, demonstrating that loss of Lkb1 was sufficient to drive the initial steps of carcinogenesis ex vivo. A similar phenotype was induced by expression of mutant K-Ras with p16/p19 deletion. Combining culture of embryonic tissues with genetic manipulation and chemical genetics thus provides a powerful approach to unraveling developmental programs and understanding cancer initiation.©2012 Lo et al. This article is distributed under the terms of an Attribution-Noncommercial- Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After sixmonths it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). © 2012 Gomez et al.

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Lo, B., Strasser, G., Sagolla, M., Austin, C. D., Junttila, M., & Mellman, I. (2012). Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways. Journal of Cell Biology, 199(7), 1117–1130. https://doi.org/10.1083/jcb.201208080

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