Role Of Activating Transcription Factor 3 Research Articles

The Response of the Prostate to Circulating Cholesterol: Activating Transcription Factor 3 (ATF3) as a Prominent Node in a Cholesterol-Sensing Network

Elevated circulating cholesterol is a systemic risk factor for cardiovascular disease and metabolic syndrome, however the manner in which the normal prostate responds to variations in cholesterol levels is poorly understood. In this study we addressed the molecular and cellular effects of elevated and suppressed levels of circulating cholesterol on the normal prostate. Integrated bioinformatic analysis was performed using DNA microarray data from two experimental formats: (1) ventral prostate from male mice with chronically elevated circulating cholesterol and (2) human prostate cells exposed acutely to cholesterol depletion. A cholesterol-sensitive gene expression network was constructed from these data and the transcription factor ATF3 was identified as a prominent node in the network. Validation experiments confirmed that elevated cholesterol reduced ATF3 expression and enhanced proliferation of prostate cells, while cholesterol depletion increased ATF3 levels and inhibited proliferation. Cholesterol reduction in vivo alleviated dense lymphomononuclear infiltrates in the periprostatic adipose tissue, which were closely associated with nerve tracts and blood vessels. These findings open new perspectives on the role of cholesterol in prostate health, and provide a novel role for ATF3, and associated proteins within a large signaling network, as a cholesterol-sensing mechanism.

The apoptotic effect of allicin in MCF‐7 human breast cancer cells: role for ATF3

Allicin induces apoptosis in various carcinoma cells and inhibits tumorigenesis. Activating transcription factor 3 (ATF3) is a stress‐inducible gene and known as a transcription factor to induce or inhibit target genes. However, the precise mechanism of allicin‐induced apoptosis is still unclear in human breast cancer cells. We investigated the effect of allicin on cell proliferation, apoptosis, and its pathway in MCF‐7 cells. MTT assay and western blotting showed that allicin decreased concentration‐dependently cell proliferation, induced apoptosis related proteins (Bax, Bid, AIF) and activated caspase‐3 and 8 in a concentration dependent manner, respectively. Our data also showed that allicin increased phosphorylation of ERK1/2, p38 and JNK in a concentration‐and time‐dependent manner and protein level of ATF3. In addition, MTT assay and western blotting showed that allicin treatment resulted in decreased cell proliferation and high level expression of apoptosis related proteins in ATF3‐overexpressed MCF‐7 cells, respectively, suggesting that ATF3 expression is involved in the regulation of allicin‐induced apoptosis. Taken together, the data suggest that allicin induces apoptosis through MAPKs and ATF3 signaling pathways in MCF‐7 cells.

ATF3 transcription factor and its emerging roles in immunity and cancer

Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding (ATF/CREB) family of transcription factors. It is an adaptive-response gene that participates in cellular processes to adapt to extra- and/or intracellular changes, where it transduces signals from various receptors to activate or repress gene expression. Advances made in understanding the immunobiology of Toll-like receptors have recently generated new momentum for the study of ATF3 in immunity. Moreover, the role of ATF3 in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.

Activating transcription factor 3 up-regulated by c-Jun NH 2-terminal kinase/c-Jun contributes to apoptosis induced by potassium deprivation in cerebellar granule neurons

Cerebellar granule neurons (CGNs) depend on potassium depolarization for survival and undergo apoptosis when deprived of depolarizing concentration of potassium. Activating transcription factor 3 (ATF3), a stress-inducible protein, belongs to the ATF/CREB family of transcription factors family and is involved in cell growth and apoptosis. However, the role of ATF3 in neuronal apoptosis remains unknown. Here, we showed that ATF3 was up-regulated under potassium deprivation in CGNs, and this induction was preceded by a rapid and sustained activation of c-Jun NH 2-terminal kinase/c-Jun signaling pathway, which plays a fundamental role in neuronal apoptosis. Furthermore, ATF3 up-regulation was abolished by inhibition of JNK or knockdown of c-Jun. Finally, knockdown of ATF3 by RNA interference protected CGNs from potassium deprivation–induced apoptosis. Taken together, our results indicate that ATF3 is a downstream target of JNK/c-Jun pathway and contributes to apoptosis induced by potassium deprivation in rat CGNs.

The Roles of ATF3 in Liver Dysfunction and the Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression

Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors, is a transcriptional repressor, and the expression of its corresponding gene, ATF3, is induced by many stress signals. In this report, we demonstrate that transgenic mice expressing ATF3 in the liver had symptoms of liver dysfunction such as high levels of serum bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bile acids. In addition, these mice had physiological responses consistent with hypoglycemia including a low insulin:glucagon ratio in the serum and reduced adipose tissue mass. Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, transient transfection assays indicated that ATF3 repressed the activity of the PEPCK promoter. Taken together, our results are consistent with the model that the expression of ATF3 in the liver results in defects in glucose homeostasis by repressing gluconeogenesis. Because ATF3 is a stress-inducible gene, these mice may provide a model to investigate the molecular mechanisms of some stress-associated liver diseases.