Stabilization of β-catenin impacts pancreas growth

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Development (Impact Factor: 6.27). 06/2006; 133(10):2023-32. DOI: 10.1242/dev.02366
Source: PubMed

ABSTRACT A recent study has shown that deletion of beta-catenin within the pancreatic epithelium results in a loss of pancreas mass. Here, we show that ectopic stabilization of beta-catenin within mouse pancreatic epithelium can have divergent effects on both organ formation and growth. Robust stabilization of beta-catenin during early organogenesis drives changes in hedgehog and Fgf10 signaling and induces a loss of Pdx1 expression in early pancreatic progenitor cells. Together, these perturbations in early pancreatic specification culminate in a severe reduction of pancreas mass and postnatal lethality. By contrast, inducing the stabilized form of beta-catenin at a later time point in pancreas development causes enhanced proliferation that results in a dramatic increase in pancreas organ size. Taken together, these data suggest a previously unappreciated temporal/spatial role for beta-catenin signaling in the regulation of pancreas organ growth.

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    • "In the adult pancreas, Wnt signalling is inactive (Pasca di Magliano et al, 2007), yet it is essential for its development during embryogenesis (Murtaugh et al, 2005; Heiser et al, 2006). The embryonic pancreas harbours multipotent progenitor cells that can give rise to all pancreatic lineages (acinar, duct and endocrine) (Zaret and Grompe, 2008). "
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    ABSTRACT: Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5(+) stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality.
    The EMBO Journal 09/2013; 32(20). DOI:10.1038/emboj.2013.204 · 10.75 Impact Factor
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    • "We analyzed the effect of MMP7 deletion on a number of Kras-driven mouse models of PDA. First, we observed Pdx1- Cre Late ; Kras G12D ; MMP7 KO and Pdx1-Cre Late ; Kras G12D ; MMP7 Het animals until a censor date of 13 months (expression pattern of Pdx-Cre Late mice previously described in (Heiser et al., 2006)). We found that all Pdx1-Cre Late ; Kras G12D ; MMP7 Het mice developed PDA (4 of 8 MMP7 Het mice succumbed to PDA before censor and the other 4 animals had PDA at the time of sacrifice) while 4 of 11 Pdx1-Cre Late ; Kras G12D ; MMP7 KO mice (36.3%) were PDA free (Figure 6B). "
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    ABSTRACT: Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.
    Cancer cell 04/2011; 19(4):441-55. DOI:10.1016/j.ccr.2011.03.002 · 23.89 Impact Factor
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    • "Thus, in our next round of experiments, we will explore in more detail the molecular mechanisms by which PAUF signaling can stabilize and activate β-catenin. Our observation that β-catenin stabilization can enhance the proliferation of pancreatic cell lines is strongly supported by other studies showing that activation of β-catenin alone is sufficient to induce pancreatic tumorigenesis using Cre/lox transgenic mice (Heiser et al., 2008), and also that deletion of the β-catenin gene results in a loss of pancreas mass during development (Heiser et al., 2006). We suggest that the rapid proliferation of pancreatic cancer cell lines can be explained at least in part by the elevated cyclin D1 and c-Jun expression caused by PAUF-induced β-catenin. "
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    ABSTRACT: It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies), contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of β-catenin while the suppression of PAUF by shRNA down-regulates β-catenin. The induction of b-catenin by PAUF is mediated by the activities of Akt and GSK-3β, but inhibition of downstream ERK does not reduce β-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of β-catenin, we examined the phosphorylation status of β-catenin in the presence of PAUF compared with that of β-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of β-catenin but no phosphorylation at Ser-45, indicating that a unique phosphorylation pattern of b-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both cyclin-D1 and c-Jun, target genes of β-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of β-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize β-catenin via a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.
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