Oleg N.Demidov1,*, Oleg Timofeev1,*, Hnin NY Lwin1, Calvina Kek1, Ettore Appella2 and Dmitry V. Bulavin1
1 Cell Cycle Control and Tumorigenesis Group, Institute of Molecular and Cell Biology, 61 Biopolis Dr., Proteos, Singapore, 138673
2 Laboratory of Cell Biology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
* These authors contributed equally.
Correspondence to DVB: email@example.com
Running title: Wip1/p53-dependent apoptosis of intestinal stem cells
Colorectal cancer is one of the major causes of cancer-related deaths. To gain further insights into the mechanisms underlying its development, we investigated the role of Wip1 phosphatase, which is highly expressed in intestinal stem cells, in the mouse model of APCMin-driven polyposis. We found that Wip1 removal increased the life-span of APCMin mice through a significant suppression of polyp formation. This protection was dependent on the p53 tumor suppressor, which plays a putative role in the regulation of apoptosis of intestinal stem cells. Activation of apoptosis in stem cells of Wip1 deficient mice, but not wild-type APCMin mice, increased when the Wnt pathway was constitutively activated. We propose that the Wip1 phosphatase regulates homeostasis of intestinal stem cells. In turn, Wip1 loss suppresses APCMin-driven polyposis by setting a threshold for p53-dependent apoptosis of stem cells, thus preventing their conversion into tumor initiating stem cells.
Published in Cell Stem Cell (2007), doi:10.1016/j.stem.2007.05.020.