Abstract:

The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.

Notes:

Rampias, TheodorosVgenopoulou, ParaskeviAvgeris, MargaritisPolyzos, AlexanderStravodimos, KonstantinosValavanis, ChristosScorilas, AndreasKlinakis, ApostolosengResearch Support, Non-U.S. Gov't2014/09/10 06:00Nat Med. 2014 Oct;20(10):1199-205. doi: 10.1038/nm.3678. Epub 2014 Sep 7.