PTEN-deficient intestinal stem cells initiate intestinal polyposis

Xi C. He, Tong Yin, Justin C. Grindley, Qiang Tian, Toshiro Sato, W. Andy Tao, Raminarao Dirisina, Kimberly S. Porter-Westpfahl, Mark Hembree, Teri Johnson, Leanne M. Wiedemann, Terrence A. Barrett, Leroy Hood, Hong Wu, Linheng Li

Research output: Contribution to journalArticle

325 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)189-198
Number of pages10
JournalNature Genetics
Volume39
Issue number2
DOIs
Publication statusPublished - 2007 Feb
Externally publishedYes

Fingerprint

Intestinal Polyposis
Phosphoric Monoester Hydrolases
Stem Cells
Catenins
Intestinal Polyps
Wnt Signaling Pathway
Neoplastic Stem Cells
Polyps
Tensins
Intestines
Neoplasms

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

He, X. C., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., ... Li, L. (2007). PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nature Genetics, 39(2), 189-198. https://doi.org/10.1038/ng1928

PTEN-deficient intestinal stem cells initiate intestinal polyposis. / He, Xi C.; Yin, Tong; Grindley, Justin C.; Tian, Qiang; Sato, Toshiro; Tao, W. Andy; Dirisina, Raminarao; Porter-Westpfahl, Kimberly S.; Hembree, Mark; Johnson, Teri; Wiedemann, Leanne M.; Barrett, Terrence A.; Hood, Leroy; Wu, Hong; Li, Linheng.

In: Nature Genetics, Vol. 39, No. 2, 02.2007, p. 189-198.

Research output: Contribution to journalArticle

He, XC, Yin, T, Grindley, JC, Tian, Q, Sato, T, Tao, WA, Dirisina, R, Porter-Westpfahl, KS, Hembree, M, Johnson, T, Wiedemann, LM, Barrett, TA, Hood, L, Wu, H & Li, L 2007, 'PTEN-deficient intestinal stem cells initiate intestinal polyposis', Nature Genetics, vol. 39, no. 2, pp. 189-198. https://doi.org/10.1038/ng1928
He, Xi C. ; Yin, Tong ; Grindley, Justin C. ; Tian, Qiang ; Sato, Toshiro ; Tao, W. Andy ; Dirisina, Raminarao ; Porter-Westpfahl, Kimberly S. ; Hembree, Mark ; Johnson, Teri ; Wiedemann, Leanne M. ; Barrett, Terrence A. ; Hood, Leroy ; Wu, Hong ; Li, Linheng. / PTEN-deficient intestinal stem cells initiate intestinal polyposis. In: Nature Genetics. 2007 ; Vol. 39, No. 2. pp. 189-198.
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