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Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas

Bonal, Claire
Ashery-Padan, Ruth
Hashimoto, Naoko
Campos, M. L.
Trumpp, Andreas
Noda, Tetsuo
Kido, Yoshiaki
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Published in Development. 2007, vol. 134, no. 15, p. 2719-2725
Abstract beta-catenin signaling is heavily involved in organogenesis. Here, we investigated how pancreas differentiation, growth and homeostasis are affected following inactivation of an endogenous inhibitor of beta-catenin, adenomatous polyposis coli (Apc). In adult mice, Apc-deficient pancreata were enlarged, solely as a result of hyperplasia of acinar cells, which accumulated beta-catenin, with the sparing of islets. Expression of a target of beta-catenin, the proto-oncogene c-myc (Myc), was increased in acinar cells lacking Apc, suggesting that c-myc expression is essential for hyperplasia. In support of this hypothesis, we found that conditional inactivation of c-myc in pancreata lacking Apc completely reversed the acinar hyperplasia. Apc loss in organs such as the liver, colon and kidney, as well as experimental misexpression of c-myc in pancreatic acinar cells, led to tumor formation with high penetrance. Surprisingly, pancreas tumors failed to develop following conditional pancreas Apc inactivation. In Apc-deficient acini of aged mice, our studies revealed a cessation of their exaggerated proliferation and a reduced expression of c-myc, in spite of the persistent accumulation of beta-catenin. In conclusion, our work shows that beta-catenin modulation of c-myc is an essential regulator of acinar growth control, and unveils an unprecedented example of Apc requirement in the pancreas that is both temporally restricted and cell-specific. This provides new insights into the mechanisms of tumor pathogenesis and tumor suppression in the pancreas.
Keywords AnimalsGenes, APC/ physiologyGenes, Tumor Suppressor/physiologyGenes, myc/physiologyGrowth/ geneticsHyperplasia/geneticsHypertrophy/geneticsMiceMice, TransgenicOrgan SpecificityPancreas/ metabolism/pathologyPancreatic Neoplasms/geneticsSignal TransductionBeta Catenin/metabolism/physiology
PMID: 17596282
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Research group Types cellulaires pancréatiques pendant l'ontogénèse (522)
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STROM, Alessandra et al. Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas. In: Development, 2007, vol. 134, n° 15, p. 2719-2725. doi: 10.1242/dev.02875 https://archive-ouverte.unige.ch/unige:9045

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Deposited on : 2010-07-12

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