Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine.
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 APC(Min)-driven polyposis. We found that Wip1 removal increased the life span of APC(Min) 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 APC(Min) mice, increased when the Wnt pathway was constitutively activated. We propose, therefore, that the Wip1 phosphatase regulates homeostasis of intestinal stem cells. In turn, Wip1 loss suppresses APC(Min)-driven polyposis by lowering the threshold for p53-dependent apoptosis of stem cells, thus preventing their conversion into tumor-initiating stem cells.
Demidov
Oleg N
ON
Cell Cycle Control and Tumorigenesis Group, Institute of Molecular and Cell Biology, Proteos 138673, Singapore.
Timofeev
Oleg
O
Lwin
Hnin N Y
HN
Kek
Calvina
C
Appella
Ettore
E
Bulavin
Dmitry V
DV
D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D007414:Intestinal Neoplasms / Q000201:enzymology* / Q000473:pathology; D007422:Intestines / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C