TY - JOUR
T1 - PTEN-deficient intestinal stem cells initiate intestinal polyposis
AU - He, Xi C.
AU - Yin, Tong
AU - Grindley, Justin C.
AU - Tian, Qiang
AU - Sato, Toshiro
AU - Tao, W. Andy
AU - Dirisina, Raminarao
AU - Porter-Westpfahl, Kimberly S.
AU - Hembree, Mark
AU - Johnson, Teri
AU - Wiedemann, Leanne M.
AU - Barrett, Terrence A.
AU - Hood, Leroy
AU - Wu, Hong
AU - Li, Linheng
N1 - Funding Information:
We are grateful to B. Neaves and R. Krumlauf for scientific support. We thank H. Okano for providing anti-Musashi1 (14-H1) and A. Ouellette for anti-cryptdin; S. Peck and G. Yang for comments on the manuscript; D. di Natale for assistance on manuscript editing; P. Kulesa and D. Stark for imaging assistance; C. Seidel, K. Zueckert-Gaudenz and M. Coleman for assistance in microarray analysis; H. Marshall for technology support and J. Chen for assistance in statistical analysis. L. Li is supported in part by research grant 5-FY05-31 from the March of Dimes Birth Defects Foundation, by grant R01 DK070001 from the National Institute of Diabetes and Digestive and Kidney Diseases and by the Stowers Institute for Medical Research.
PY - 2007/2
Y1 - 2007/2
N2 - Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector β-catenin. Akt phosphorylates β-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of β-catenin.
AB - Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector β-catenin. Akt phosphorylates β-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of β-catenin.
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U2 - 10.1038/ng1928
DO - 10.1038/ng1928
M3 - Article
C2 - 17237784
AN - SCOPUS:33846600427
SN - 1061-4036
VL - 39
SP - 189
EP - 198
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -