The transcription factor NFAT1 induces apoptosis through cooperation with Ras/Raf/MEK/ERK pathway and upregulation of TNF-α expression

• Published in: Biochimica et biophysica acta 2013-08, Vol.1833 (8), p.2016-2028
• Main Authors: Robbs, Bruno K., Lucena, Pedro I., Viola, João P.B.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Caspases - genetics; Caspases - metabolism; Cell death; Cell Death - genetics; Cell Line; ERK; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; Mice; Necrosis - genetics; Necrosis - metabolism; NFAT; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; NIH 3T3 Cells; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Ras; ras Proteins - genetics; ras Proteins - metabolism; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; TNF-α; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor suppressor; Up-Regulation
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2013.04.003

Nuclear factor of activated T cells (NFAT) was described as an activation and differentiation factor in T cells. NFAT1 protein is expressed in several cell types and has been implicated in the control of the cell cycle, death and migration. Overexpression or activation of NFAT1 has been demonstrated to induce cell death in different cell types, such as T lymphocytes, Burkitt's lymphoma, and fibroblasts. Although these findings indicate a role for NFAT1 transcription factor in control of cell death, the precise mechanisms involved in this process regulated by NFAT1 are still poorly understood. The Ras/Raf/MEK/ERK pathway is activated by many growth factors and cytokines that are important in driving proliferation and preventing apoptosis and is widely implicated in cell transformation and cancer development. We show that NFAT1 protein can cooperate with Ras/Raf/MEK/ERK, but not with the JNK, p38 or NFκB pathways in cell death induction. NFAT1 can induce a cell death pathway consistent with apoptosis, which can be shifted to programmed necrosis by caspase inhibitors. Finally, through screening genes involved in cell death regulation, although we determined that TNF-α, TRAIL and PAK7 genes were up-regulated, only TNF-α expression was responsible for cell death in this context. These data suggest that NFAT1 protein activation can shift oncogenic Ras/Raf/MEK/ERK signaling to acting as a tumor suppressor pathway. These data support a potential role for regulating NFAT1 expression in gene therapy in tumors that display an activated Ras pathway, which could lead to more specific, target-directed TNF-α expression and, thus, tumor suppression. •NFAT1 protein induces cell death in cooperation with Ras/MAPK pathway.•NFAT1 cooperates with MEK/ERK pathway but not with JNK, p38 or NFκB pathways.•NFAT1 induced cell death was phenotypically characterized as apoptosis.•TNF-α upregulation was the main cause of cell death controlled by NFAT1.•NFAT1 expression could be exploited in cancer gene therapy with activated ERK pathway.