PTEN-deficient Intestinal Stem Cells Initiate Intestinal Polyposis

Overview

Journal Nat Genet

Specialty Genetics

Date 2007 Jan 24

PMID 17237784

Citations 244

Authors

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

Affiliations

Soon will be listed here.

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 beta-catenin. Akt phosphorylates beta-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 beta-catenin.

Citing Articles

Microbial metabolites control self-renewal and precancerous progression of human cervical stem cells.

Myeong J, Lee M, Lee B, Kim J, Nam Y, Choi Y Nat Commun. 2025; 16(1):2327.

PMID: 40057497 PMC: 11890575. DOI: 10.1038/s41467-025-57323-6.

SLC1A4 Promotes Malignant Transformation of Hepatocellular Carcinoma by Activating the AKT Signaling.

Zheng J, Gong J Anal Cell Pathol (Amst). 2025; 2025:1115184.

PMID: 39949345 PMC: 11824774. DOI: 10.1155/ancp/1115184.

Investigating the Interplay Between the Nrf2/Keap1/HO-1/SIRT-1 Pathway and the p75NTR/PI3K/Akt/MAPK Cascade in Neurological Disorders: Mechanistic Insights and Therapeutic Innovations.

Mukherjee R, Rana R, Mehan S, Khan Z, Gupta G, Narula A Mol Neurobiol. 2025; .

PMID: 39920438 DOI: 10.1007/s12035-025-04725-8.

Wnt Signaling Pathway in Tumor Biology.

Iluta S, Nistor M, Buruiana S, Dima D Genes (Basel). 2025; 15(12.

PMID: 39766864 PMC: 11675244. DOI: 10.3390/genes15121597.

Human colonic organoids for understanding early events of familial adenomatous polyposis pathogenesis.

Laborde N, Barusseaud A, Quaranta M, Rolland C, Arrouy A, Bonnet D J Pathol. 2024; 265(1):26-40.

PMID: 39641466 PMC: 11638664. DOI: 10.1002/path.6366.

References

Waite K, Eng C . BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. 2003; 12(6):679-84. View

Howe J, Bair J, Sayed M, Anderson M, Mitros F, Petersen G . Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001; 28(2):184-7. DOI: 10.1038/88919. View

Groszer M, Erickson R, Lesche R, Trumpp A, Zack J, Kornblum H . Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science. 2001; 294(5549):2186-9. DOI: 10.1126/science.1065518. View

van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H . Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem. 2002; 277(20):17901-5. DOI: 10.1074/jbc.M111635200. View

Wirtzfeld D, Petrelli N, Rodriguez-Bigas M . Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann Surg Oncol. 2001; 8(4):319-27. DOI: 10.1007/s10434-001-0319-7. View

Wong W, Mandir N, Goodlad R, Wong B, Garcia S, Lam S . Histogenesis of human colorectal adenomas and hyperplastic polyps: the role of cell proliferation and crypt fission. Gut. 2002; 50(2):212-7. PMC: 1773120. DOI: 10.1136/gut.50.2.212. View

Wasan H, Park H, Liu K, Mandir N, Winnett A, Sasieni P . APC in the regulation of intestinal crypt fission. J Pathol. 1998; 185(3):246-55. DOI: 10.1002/(SICI)1096-9896(199807)185:3<246::AID-PATH90>3.0.CO;2-8. View

Potten C, Owen G, Booth D . Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci. 2002; 115(Pt 11):2381-8. DOI: 10.1242/jcs.115.11.2381. View

Persad S, Troussard A, McPhee T, Mulholland D, Dedhar S . Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation. J Cell Biol. 2001; 153(6):1161-74. PMC: 2192018. DOI: 10.1083/jcb.153.6.1161. View

10.

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Minden M . A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367(6464):645-8. DOI: 10.1038/367645a0. View

11.

Gera J, Mellinghoff I, Shi Y, Rettig M, Tran C, Hsu J . AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem. 2003; 279(4):2737-46. DOI: 10.1074/jbc.M309999200. View

12.

Tian Q, Feetham M, Tao W, He X, Li L, Aebersold R . Proteomic analysis identifies that 14-3-3zeta interacts with beta-catenin and facilitates its activation by Akt. Proc Natl Acad Sci U S A. 2004; 101(43):15370-5. PMC: 524456. DOI: 10.1073/pnas.0406499101. View

13.

Potten C, Booth C, Tudor G, Booth D, Brady G, Hurley P . Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation. 2003; 71(1):28-41. DOI: 10.1046/j.1432-0436.2003.700603.x. View

14.

Liaw D, Marsh D, Li J, Dahia P, Wang S, Zheng Z . Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997; 16(1):64-7. DOI: 10.1038/ng0597-64. View

15.

Tetsu O, McCormick F . Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999; 398(6726):422-6. DOI: 10.1038/18884. View

16.

Stiles B, Groszer M, Wang S, Jiao J, Wu H . PTENless means more. Dev Biol. 2004; 273(2):175-84. DOI: 10.1016/j.ydbio.2004.06.008. View

17.

Haramis A, Begthel H, van den Born M, van Es J, Jonkheer S, Offerhaus G . De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004; 303(5664):1684-6. DOI: 10.1126/science.1093587. View

18.

Megy S, Bertho G, Gharbi-Benarous J, Baleux F, Benarous R, Girault J . Solution structure of a peptide derived from the oncogenic protein beta-Catenin in its phosphorylated and nonphosphorylated states. Peptides. 2005; 26(2):227-41. DOI: 10.1016/j.peptides.2004.09.021. View

19.

Huber A, Nelson W, Weis W . Three-dimensional structure of the armadillo repeat region of beta-catenin. Cell. 1997; 90(5):871-82. DOI: 10.1016/s0092-8674(00)80352-9. View

20.

Asai R, Okano H, Yasugi S . Correlation between Musashi-1 and c-hairy-1 expression and cell proliferation activity in the developing intestine and stomach of both chicken and mouse. Dev Growth Differ. 2005; 47(8):501-10. DOI: 10.1111/j.1440-169X.2005.00825.x. View