Article abstract
Nature Genetics 39, 189 - 198 (2007)
Published online: 21 January 2007 | doi:10.1038/ng1928
PTEN-deficient intestinal stem cells initiate intestinal polyposis
Xi C He1, Tong Yin1, Justin C Grindley1, Qiang Tian2, Toshiro Sato1, W Andy Tao3, Raminarao Dirisina4, Kimberly S Porter-Westpfahl1, Mark Hembree1, Teri Johnson1, Leanne M Wiedemann1,5, Terrence A Barrett4, Leroy Hood2, Hong Wu6 & Linheng Li1,5
Abstract
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 
-catenin. Akt phosphorylates -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 -catenin.
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.
- Institute for Systems Biology, Seattle, Washington 98103, USA.
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.
- Department of Medicine and Microbiology/Immunology, Division of Gastroenterology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
- Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, Kansas 66160, USA.
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, California 90095, USA.
Correspondence to: Linheng Li1,5 e-mail: lil@stowers-institute.org
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