Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NF kappa B-dependent pathway.
Mitogen-activated protein kinase kinase-4 (MKK4/SEK1) cooperates with phosphatidylinositol 3-kinase 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 prosurvival 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 NFkappaB, a transcriptional suppressor of PTEN. MKK4 was required for nuclear translocation of RelA/p65 and processing of the NFkappaB2 precursor (p100) into the mature form (p52). Studies on a panel of NSCLC cell lines revealed a subset with high MKK4/high NFkappaB/low PTEN that was relatively resistant to apoptosis. Thus, MKK4 promotes cell survival by activating phosphatidylinositol 3-kinase through an NFkappaB/PTEN-dependent pathway.
Xia
Dianren
D
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M D Anderson Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Srinivas
Harish
H
Ahn
Young-Ho
YH
Sethi
Gautam
G
Sheng
Xiaoyang
X
Yung
W K Alfred
WK
Xia
Qianghua
Q
Chiao
Paul J
PJ
Kim
Heetae
H
Brown
Powel H
PH
Wistuba
Ignacio I
II
Aggarwal
Bharat B
BB
Kurie
Jonathan M
JM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D048670:MAP Kinase Kinase 4; D051059:PTEN Phosphohydrolase