1. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5-triphosphate and Akt/protein kinase B signaling pathway
- Author
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Sun, Hong, Lesche, Ralf, Li, Da-Ming, Liliental, Joanna, Zhang, Hui, Gao, Jing, Gavrilova, Nadia, Mueller, Brenda, Liu, Xin, and Wu, Hong
- Subjects
Tumor suppressor genes -- Research ,Phosphoinositides -- Physiological aspects ,Protein kinases -- Physiological aspects ,Gene mutations -- Research ,Cancer -- Genetic aspects ,Science and technology - 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.sup.-/-] 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 [G.sub.1]/S transition was accompanied by down-regulation of [p27.sup.KIP1], a major inhibitor for [G.sub.1] 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.sup.-/-] 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.
- Published
- 1999