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PMID:17596282
| Citation |
Strom, A, Bonal, C, Ashery-Padan, R, Hashimoto, N, Campos, ML, Trumpp, A, Noda, T, Kido, Y, Real, FX, Thorel, F and Herrera, PL (2007) Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas. Development 134:2719-25 |
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| 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. |
| Links |
PubMed Online version:10.1242/dev.02875 |
| Keywords |
Animals; Genes, APC/physiology; Genes, Tumor Suppressor/physiology; Genes, myc/physiology; Growth/genetics; Hyperplasia/genetics; Hypertrophy/genetics; Mice; Mice, Transgenic; Organ Specificity; Pancreas/metabolism; Pancreas/pathology; Pancreatic Neoplasms/genetics; Signal Transduction; beta Catenin/metabolism; beta Catenin/physiology |
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Significance
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