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First published online 27 June 2007
doi: 10.1242/dev.02875
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Research Report |
1 Department of Genetic Medicine and Development, University of Geneva Faculty
of Medicine, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
2 Department of Human Molecular Genetics and Biochemistry, Sackler School of
Medicine, Tel-Aviv University, Israel.
3 Department of Cell Biology, Cancer Institute, Tokyo 135-8550, Japan.
4 Unitat de Recerca en Biologia Cel·lular i Molecular (URBCM), Institut
Municipal d'Investigació Mèdica (IMIM), Universitat Pompeu
Fabra, Dr Aiguader, 88 08003 Barcelona, Spain.
5 Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer
Research (ISREC), Ch. des Boveresses 155, CH-1066 Epalinges,
Switzerland.
6 Division of Diabetes, Digestive and Kidney Disease, Division of Diabetes
Metabolism and Endocrinology, Department of Clinical Molecular Medicine,
Department of Internal Medicine, Kobe University Graduate School of Medicine,
7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
7 Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life
Sciences, CH-1015 Lausanne, Switzerland.
* Author for correspondence (e-mail: Pedro.Herrera{at}medecine.unige.ch)
Accepted 18 May 2007
SUMMARY
ß-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 ß-catenin, adenomatous polyposis coli (Apc). In adult mice, Apc-deficient pancreata were enlarged, solely as a result of hyperplasia of acinar cells, which accumulated ß-catenin, with the sparing of islets. Expression of a target of ß-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 ß-catenin. In conclusion, our work shows that ß-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.
Key words: Pancreas, Growth, Apc, ß-catenin, c-myc, ICAT, Mouse
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