Philip E. Dubé
University of Toronto
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Featured researches published by Philip E. Dubé.
Endocrinology | 2011
Jason Leen; Angelo Izzo; Chandani Upadhyay; Katherine J. Rowland; Philip E. Dubé; Steven Gu; Scott P. Heximer; Christopher J. Rhodes; Daniel R. Storm; P. Kay Lund; Patricia L. Brubaker
IGF-I, a known secretory product of intestinal subepithelial myofibroblasts (ISEMFs), is essential for the intestinotropic effects of glucagon-like peptide-2 (GLP-2). Furthermore, GLP-2 increases IGF-I mRNA transcript levels in vitro in heterogeneous fetal rat intestinal cultures, as well as in vivo in the rodent small intestine. To determine the mechanism underlying the stimulatory effect of GLP-2 on intestinal IGF-I mRNA, murine ISEMF cells were placed into primary culture. Immunocytochemistry showed that the ISEMF cells appropriately expressed α-smooth muscle actin and vimentin but not desmin. The cells also expressed GLP-2 receptor and IGF-I mRNA transcripts. Treatment of ISEMF cells with (Gly2)GLP-2 induced IGF-I mRNA transcripts by up to 5-fold of basal levels after treatment with 10(-8) m GLP-2 for 2 h (P < 0.05) but did not increase transcript levels for other intestinal growth factors, such as ErbB family members. Immunoblot revealed a 1.6-fold increase in phospho (p)-Akt/total-(t)Akt with 10(-8) m GLP-2 treatment (P < 0.05) but no changes in cAMP, cAMP-dependent β-galactosidase expression, pcAMP response element-binding protein/tcAMP response element-binding protein, pErk1/2/tErk1/2, or intracellular calcium. Furthermore, pretreatment of ISEMF cells with the phosphatidylinositol 3 kinase (PI3K) inhibitors, LY294002 and wortmannin, abrogated the IGF-I mRNA response to GLP-2, as did overexpression of kinase-dead Akt. The role of PI3K/Akt in GLP-2-induced IGF-I mRNA levels in the murine jejunum was also confirmed in vivo. These findings implicate the PI3K/Akt pathway in the stimulatory effects of GLP-2 to enhance intestinal IGF-I mRNA transcript levels and provide further evidence in support of a role for IGF-I produced by the ISEMF cells in the intestinotropic effects of GLP-2.
FEBS Journal | 2005
Liang Chen; Peixiang Wang; Cristiano Feijó Andrade; Ian Y. Zhao; Philip E. Dubé; Patricia L. Brubaker; Mingyao Liu; Tianru Jin
Cdx‐2 is a transactivator for the proglucagon gene in pancreatic and intestinal endocrine cells. Cdx‐2 is also expressed in differentiated intestinal epithelia of nonendocrine origin. Cdx‐2–/– mice are embryonic lethal, while Cdx‐2+/– mutants show multiple malfunctions including the formation of intestinal polyps. Within the polyps, the remaining wild type Cdx‐2 allele ceases its expression, while the expression of both Cdx‐2 and proglucagon in the endocrine cells remains unaltered, indicating that Cdx‐2 could be haplo‐insufficient for nonendocrine cells, but not for proglucagon producing endocrine cells. We propose that mechanisms underlying Cdx‐2 expression and auto‐regulation [Xu F, Li H & Jin T (1999), J Biol Chem274, 34310–34316] differ in these two types of cells. We show here that forskolin and cAMP upregulate Cdx‐2 expression in proglucagon producing cells, but not in colon cancer cells and primary intestinal cell cultures. It is unlikely that the activation is mainly mediated by PKA, because the activation was observed in a PKA deficient cell line. Cotransfecting a dominant negative Ras expression plasmid substantially repressed the Cdx‐2 promoter, in contrast to a previous finding that Ras is a negative factor for Cdx‐2 expression in colon cancer cells. Furthermore, forskolin activated ERK1/2 phosphorylation in the endocrine cells, and attenuation of ERK1/2 phosphorylation by its inhibitor is associated with attenuated Cdx‐2 expression. Finally, an Epac pathway specific cAMP analogue stimulated both ERK1/2 phosphorylation and Cdx‐2 expression. Taken together, our observations suggest that Cdx‐2 expression is regulated by the second messenger cAMP, cell‐type specifically, via the Epac pathway.
Gastroenterology | 2011
Shivesh Punit; Philip E. Dubé; Kay Washington; D. Brent Polk
G A A b st ra ct s led to the significant reduction of both IL-17-producing LincKitThy1+ Sca1+ innate lymphoid cells and IL-17-producing CD4+ T cells in the colon of Muc1-deficient TCR alpha double KO mice. Since Muc1 was proposed previously to play an inflammatory role in a Th1-mediated colitis of IL-10 KO mice, we next examined the role of Muc1 in another Th1mediated colitis model, CD45RB model. As seen in TCR alpha KO mice, absence of Muc1 further enhanced Th17 responses and exacerbated the colitis in recipient Muc1-deficient RAG1 double KO mice (as compared to recipient RAG1 KO mice) after transfer of naïve CD4+ T cells from WT mice. Conclusion: A membrane-bound mucin functions as a key determinant of colitis-associated Th17 responses and seems to contribute to the suppression of both Th2and Th1-mediated colitis.
Gastroenterology | 2006
Philip E. Dubé; Catherine L. Forse; Jasmine Bahrami; Patricia L. Brubaker
American Journal of Physiology-endocrinology and Metabolism | 2007
Philip E. Dubé; Patricia L. Brubaker
Endocrinology | 2008
Philip E. Dubé; Katherine J. Rowland; Patricia L. Brubaker
Gastroenterology | 2017
Sharon S. Tam; Nandini Girish; Philip E. Dubé; Rabea Alhosh; Shivesh Punit; Cambrian Y. Liu; Kay Washington; D. Brent Polk
Gastroenterology | 2017
Cambrian Y. Liu; Philip E. Dubé; Nandini Girish; Shivesh Punit; Kay Washington; D. Brent Polk
Gastroenterology | 2017
Shivesh Punit; Philip E. Dubé; Cambrian Y. Liu; Nandini Girish; Ying Huang; Kay Washington; D. Brent Polk
Gastroenterology | 2016
Philip E. Dubé; Shivesh Punit; Nandini Girish; Kay Washington; D. Brent Polk