Mitogen -activated protein kinase kinase-4 maintains cell survival through NFκB-dependent inhibition of PTEN gene expression
Mitogen-activated protein kinase kinase-4 (MKK4/SEK1) cooperates with phosphatidylinositol 3-kinase (P13K) to maintain the survival of non-small cell lung cancer (NSCLC) cells, but the biochemical basis of this phenomenon has not been elucidated. Here we used genetic approaches to modulate MKK4 expression in mouse embryo fibroblasts (MEF cells) and NSCLC cells to identify pro-survival signals downstream of MKK4. Relative to wild-type MEF cells, MKK4-null MEF cells were highly susceptible to apoptosis by LY294002, paclitaxel, or serum starvation. MKK4 promoted the survival of MEF cells by decreasing the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN). MKK4 inhibited PTEN transcription by activating NFκB, a transcriptional suppressor of PTEN. Studies on a panel of NSCLC cell lines revealed a subset with high MKK4/high NFκB/low PTEN that was relatively resistant to apoptosis. Thus, MKK4 promotes cell survival by activating P13K through an NFκB/PTEN-dependent pathway.
Xia, Dianren, "Mitogen -activated protein kinase kinase-4 maintains cell survival through NFκB-dependent inhibition of PTEN gene expression" (2006). Texas Medical Center Dissertations (via ProQuest). AAI3231750.