The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor kappa B activity.
Nuclear factor kappaB (NF-kappaB) transcriptionally activates genes that promote immunity and cell survival. Activation of NF-kappaB is induced by an IkappaB kinase (IKK) complex that phosphorylates and promotes dissociation of IkappaB from NF-kappaB, which then translocates into the nucleus. Activation of phosphatidylinositol (PI) 3-kinase/Akt signaling by tumor necrosis factor (TNF) activates IKK and NF-kappaB. The present study shows that PTEN, a tumor suppressor that inhibits PI 3-kinase function, impairs TNF activation of Akt and the IKK complex in 293 cells. Transient expression of PTEN suppressed IKK activation and TNF-induced NF-kappaB DNA binding and transactivation. Studies were conducted with PC-3 prostate cancer cells that do not express PTEN and DU145 prostate cancer cells that express PTEN. TNF activated Akt in PC-3 cells, but not in DU145 cells, and the ability of TNF to activate NF-kappaB was blocked by pharmacological inhibition of PI 3-kinase activity in PC-3 cells, but not in DU145 cells. Expression of PTEN in PC-3 cells to a level comparable with that endogenously present in DU145 cells inhibited TNF activation of NF-kappaB. The cell type-specific ability of PTEN to negatively regulate the PI 3-kinase/AKT/NF-kappaB pathway may be important to its tumor suppressor activity.
Gustin
J A
JA
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Maehama
T
T
Dixon
J E
JE
Donner
D B
DB
D002460:Cell Line; D016147:Genes, Tumor Suppressor; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins
D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human