Suppression of PTEN expression by NF-kappa B prevents apoptosis.
NF-kappa B is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-kappa B prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes. We report here that the tumor suppressor PTEN, which functions as a negative regulator of phosphatidylinositol (PI)-3 kinase/Akt-mediated cell survival pathway, is down regulated by p65 but not by p50. Moreover, a subset of human lung or thyroid cancer cells expressing high levels of endogenous p65 showed decreased expression of PTEN that could be rescued by specific inhibition of the NF-kappa B pathway with I kappa B overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-kappa B activity, suppressed PTEN gene expression in IKK beta(+/+) cells but not in IKK beta(-/-) cells, which are deficient in the NF-kappa B activation pathway. These findings indicated that NF-kappa B activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-kappa B. The mechanism underlying suppression of PTEN expression by NF-kappa B was independent of p65 DNA binding or transcription function and involved sequestration of limiting pools of transcriptional coactivators CBP/p300 by p65. Restoration of PTEN expression inhibited NF-kappa B transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-kappa B. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-kappa B.
Vasudevan
Krishna Murthi
KM
Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536, USA.
Gurumurthy
Sushma
S
Rangnekar
Vivek M
VM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D009687:Nuclear Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human