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PMID: 10339565 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 11 ·1999-05-25 ·Pages 6199-204

Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H

Abstract

To investigate the molecular basis of PTEN-mediated tumor suppression, we introduced a null mutation into the mouse Pten gene by homologous recombination in embryonic stem (ES) cells. Pten-/- ES cells exhibited an increased growth rate and proliferated even in the absence of serum. ES cells lacking PTEN function also displayed advanced entry into S phase. This accelerated G1/S transition was accompanied by down-regulation of p27(KIP1), a major inhibitor for G1 cyclin-dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts resulted in elevated levels of phosphatidylinositol 3,4,5,-trisphosphate, a product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to dosage-dependent increases in phosphorylation and activation of Akt/protein kinase B, a well-characterized target of the phosphatidylinositol 3 kinase signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten-/- cell survival. Our studies suggest that PTEN regulates the phosphatidylinositol 3,4, 5,-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival.

MeSH Terms
Animals Cell Cycle/physiology Cell Cycle Proteins Cell Division Cell Survival Cells, Cultured Cyclin-Dependent Kinase Inhibitor p27 Embryo, Mammalian Genes, Tumor Suppressor Genomic Library In Situ Nick-End Labeling Kinetics Mice Mice, Knockout Microtubule-Associated Proteins/genetics,metabolism PTEN Phosphohydrolase Phosphatidylinositol Phosphates/metabolism Phosphoric Monoester Hydrolases/deficiency,genetics,physiology Protein Serine-Threonine Kinases Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Recombination, Genetic Restriction Mapping Signal Transduction Stem Cells/cytology Tumor Suppressor Proteins
Chemicals
Cdkn1b protein, mouse Cell Cycle Proteins Microtubule-Associated Proteins Phosphatidylinositol Phosphates Proto-Oncogene Proteins Tumor Suppressor Proteins phosphatidylinositol 3,4,5-triphosphate Cyclin-Dependent Kinase Inhibitor p27 Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Phosphoric Monoester Hydrolases PTEN Phosphohydrolase
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sun H
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Lesche R
Li D M
Liliental J
Zhang H
Gao J
Gavrilova N
Mueller B
Liu X
Wu H
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.11.6199
Published
1999-05-25
Pages
6199-204
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC26859
Subset
IM
Grants
NCI NIH HHS · CA72878 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.11.6199 PMC Full Text View journal details
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