Growth factor regulation of prostaglandin-endoperoxide synthase 2 (Ptgs2) expression in colonic mesenchymal stem cells.
ABSTRACT We previously found that a population of colonic stromal cells that constitutively express high levels of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2) altered their location in the lamina propria in response to injury in a Myd88-dependent manner (Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., and Stappenbeck, T. S. (2007) J. Clin. Invest. 117, 258-269). At the time of this study, the identity of these cells and the mechanism by which they expressed high levels of Ptgs2 were unknown. Here we found that these colonic stromal cells were mesenchymal stem cells (MSCs). These colonic MSCs expressed high Ptgs2 levels not through interaction with bacterial products but instead as a consequence of mRNA stabilization downstream of Fgf9 (fibroblast growth factor 9), a growth factor that is constitutively expressed by the intestinal epithelium. This stabilization was mediated partially through a mechanism involving endogenous CUG-binding protein 2 (CUGbp2). These studies suggest that Fgf9 is an important factor in the regulation of Ptgs2 in colonic MSCs and may be a factor involved in its constitutive expression in vivo.
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ABSTRACT: The tumor microenvironment presents an exciting opportunity for innovative prognostic and therapeutic approaches to human cancer. The diverse cellular and extracellular contribution to tumor growth argues that prevention and cure of human cancers will result only from a multifaceted approach to cancer therapy. In this review we provide a foundation for considering the mesenchymal contribution to the tumor microenvironment. We address normal mesenchymal development, physiological interactions between the epithelium and stroma and the cellular hierarchy within these compartments. We focus on cancer-associated fibroblasts in gastrointestinal malignancy but our models have also been informed by other tumor systems. The review provides a framework for characterizing the overall biological contribution of the mesenchyme to human disease. Understanding the biological heterogeneity of specific mesenchymal cells in cancer will provide new opportunities for targeted cancer prevention and therapy.Pharmacology [?] Therapeutics 08/2012; 136(2):131-41. · 7.79 Impact Factor
Article: CELFish ways to modulate mRNA decay.[Show abstract] [Hide abstract]
ABSTRACT: The CELF family of RNA-binding proteins regulates many steps of mRNA metabolism. Although their best characterized function is in pre-mRNA splice site choice, CELF family members are also powerful modulators of mRNA decay. In this review we focus on the different modes of regulation that CELF proteins employ to mediate mRNA decay by binding to GU-rich elements. After starting with an overview of the importance of CELF proteins during development and disease pathogenesis, we then review the mRNA networks and cellular pathways these proteins regulate and the mechanisms by which they influence mRNA decay. Finally, we discuss how CELF protein activity is modulated during development and in response to cellular signals. We conclude by highlighting the priorities for new experiments in this field. This article is part of a Special Issue entitled: RNA Decay mechanisms.Biochimica et Biophysica Acta 01/2013; · 4.66 Impact Factor
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ABSTRACT: Predominant transcriptional subnetworks called Core, Myc, and PRC modules have been shown to participate in preservation of the pluripotency and self-renewality of embryonic stem cells (ESCs). Epiblast stem cells (EpiSCs) are another cell type that possesses pluripotency and self-renewality. However, the roles of these modules in EpiSCs have not been systematically examined to date. Here, we compared the average expression levels of Core, Myc, and PRC module genes between ESCs and EpiSCs. EpiSCs showed substantially higher and lower expression levels of PRC and Core module genes, respectively, compared with those in ESCs, while Myc module members showed almost equivalent levels of average gene expression. Subsequent analyses revealed that the similarity in gene expression levels of the Myc module between these two cell types was not just overall, but striking similarities were evident even when comparing the expression of individual genes. We also observed equivalent levels of similarity in the expression of individual Myc module genes between induced pluripotent stem cells (iPSCs) and partial iPSCs that are an unwanted byproduct generated during iPSC induction. Moreover, our data demonstrate that partial iPSCs depend on a high level of c-Myc expression for their self-renewal properties.PLoS ONE 01/2013; 8(12):e83769. · 3.53 Impact Factor