Suppression of PTEN expression by NF-κB prevents apoptosis

NF-kappaB is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-kappaB 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-kappaB pathway with IkappaB overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-kappaB activity, suppressed PTEN gene expression in IKKP+/(+) cells but not in IKKbeta(-/-) cells, which are deficient in the NF-kappaB activation pathway. These findings indicated that NF-kappaB activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-kappaB. The mechanism underlying suppression of PTEN expression by NF-kappaB 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-kappaB transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-kappaB. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-kappaB.