Regenerating Reputations: Are Wnt and Myc the Good Guys After All?
Regenerating Reputations: Are Wnt and Myc the Good Guys After All?
复制标题
重获声誉：Wnt 和 Myc 到底是好人吗？
DOI：
10.1007/s10620-015-3947-7
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发表时间：
2016
影响因子：
3.1
通讯作者：
Frey,MarkR
中科院分区：
文献类型：
--
作者：
Frey,MarkR
Inflammatory bowel disease (IBD) is one of the biggest challenges facing gastroenterologists today, due to the lack of efficacy of many of its treatments, its widespread morbidities, and its increasing incidence [1]. One of the etiological factors thought to contribute to IBD pathogenesis is diminished intestinal barrier function, which at least in theory permits luminal antigens such as bacterial products to enter the submucosa [2]. Hence, a major unmet need in IBD treatment is a strategy to reverse barrier breaches by directly promoting mucosal restitution and repair. While the importance of this endpoint has been widely acknowledged [3], no IBD therapies currently in use directly target regeneration of the intestinal or colonic epithelium. Rather, it is currently a case of ‘‘Mucosa, heal thyself!’’in which repair is expected to occur secondarily to the blockade of inflammation. Nevertheless, a wounded mucosa and its attendant disrupted barrier are thought to contribute to ongoing inflammation. Thus, directly bolstering mucosal regeneration may provide an improved alternative or adjunct approach to IBD treatment. In this issue of Digestive Diseases and Sciences, Raup-Konsavage and colleagues report proof-of-concept data supporting pharmacologically targeting glycogen synthase kinase (GSK)-3b to promote intestinal repair and regeneration through a c-Myc-dependent pathway [4]. The Wnt signaling pathway and the Myc transcription factor are central regulators of cell division that for years have been theoretical clinical targets. They have typically been investigated as targets for inhibition, due to the strongly oncogenic effects of constitutively activating mutants. However, an emerging literature suggests that harnessing these pathways’ ability to promote cell division could be an effective therapeutic approach for the treatment of injury and inflammation, including in the gut. The Yochum laboratory has previously characterized a mouse with a deletion in the 30 Wnt responsive DNA element of the Myc gene [5]. This mouse displayed a moderate increase in Myc protein expression, heightened intestinal crypt proliferation, and accelerated recovery from dextran sulfate sodium (DSS)-induced experimental colitis. Thus, in the current study, they tested whether indirectly inducing Myc by pharmacologically activating Wnt signaling with LiCl promotes healing. The data show that LiCl does indeed stimulate recovery when given to mice with established acute DSS colitis, and that this protection is sensitive to pharmacological Myc inhibition. The authors also demonstrated direct effects of LiCl and Myc on epithelial cells in vitro by observing lithium-induced accelerated scratch assay restitution, which was reversed by the Myc inhibitor. They consequently outline a surprisingly specific pathway driving recovery from an inflammatory insult in the gut, using a drug related to compounds already widely used in human patients with psychiatric disorders, such as Li2CO3.
