The Tumor Suppressor Protein TEP1/PTEN/MMAC1 and Human Breast Cancer
Abstract
PTEN is an important tumor suppressor that is commonly mutated in a wide variety of human cancers. Recent studies have suggested that the PTEN protein can in vitro dephosphorylate phosphatidylinositol-3,4,5-trisphosphate (PIP3), a product of PI 3-kinase. We have generated mouse embryonic stem (ES) cells in which either one or both copies of the PTEN genes were deleted. Using the isogenic PTEN+/+ and PTEN-/- cells, we showed that PTEN deficiency leads to an increase of PIP3 levels and enhanced activation of Akt, indicating that PTEN indeed negatively regulates the PI 3-kinase/Akt signaling pathway in vivo. Characterization of PTEN+/+ and PTEN-/- ES cells further demonstrated that PTEN regulates two critical cellular processes: cell cycle progression and apoptosis. PTEN-/- ES cells exhibit an advanced S-phase entry and the marked decrease in levels of p27KIP 1, an inhibitor for cyclin-dependent kinases. We have further shown that expression of PTEN in PTEN-deficient human glioblastoma cells causes Gi cell cycle arrest and accumulation of p27KW 1. Our studies suggest that PTEN in vivo regulates PI 3-kinase signaling pathway and a critical target for this pathway is p27KIPl. p27KIPl is a well known prognosis marker for human breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 1999
- Accession Number
- ADA385901
Entities
People
- Hong Sun
Organizations
- Yale University