Down-regulation of the tumor suppressor PTEN by the tumor necrosis factor-alpha/nuclear factor-kappaB (NF-kappaB)-inducing kinase/NF-kappaB pathway is linked to a default IkappaB-alpha autoregulatory loop.
Fiche publication
Date publication
février 2004
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DOMON-DELL Claire, Dr FREUND Jean-Noël
Tous les auteurs :
Kim S, Domon-Dell C, Kang J, Chung DH, Freund JN, Evers BM
Lien Pubmed
Résumé
The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene affects multiple cellular processes including cell growth, proliferation, and cell migration by antagonizing phosphatidylinositol 3-kinase (PI3K). However, mechanisms by which PTEN expression is regulated have not been studied extensively. Similar to PTEN, tumor necrosis factor-alpha (TNF-alpha) affects a wide spectrum of diseases including inflammatory processes and cancer by acting as a mediator of apoptosis, inflammation, and immunity. In this study, we show that treatment of cancer cell lines with TNF-alpha decreases PTEN expression. In addition, overexpression of TNF-alpha downstream signaling targets, nuclear factor-kappaB (NF-kappaB)-inducing kinase (NIK) and p65 nuclear factor NF-kappaB, lowers PTEN expression, suggesting that TNF-alpha-induced down-regulation of PTEN is mediated through a TNF-alpha/NIK/NF-kappaB pathway. Down-regulation of PTEN by NIK/NF-kappaB results in activation of the PI3K/Akt pathway and augmentation of TNF-alpha-induced PI3K/Akt stimulation. Importantly, we demonstrate that this effect is associated with a lack of an inhibitor of kappaB (IkappaB)-alpha autoregulatory loop. Moreover, these findings suggest the interaction between PI3K/Akt and NF-kappaB via transcriptional regulation of PTEN and offer one possible explanation for increased tumorigenesis in systems in which NF-kappaB is chronically activated. In such a tumor system, these findings suggest a positive feedback loop whereby Akt activation of NF-kappaB further stimulates Akt via down-regulation of the PI3K inhibitor PTEN.
Référence
J Biol Chem. 2004 Feb 6;279(6):4285-91