Activating transcription factor-2 regulates phosphoenolpyruvate carboxykinase transcription through a stress-inducible mitogen-activated protein kinase pathway.
Several protein-nucleic acid complexes are observed when nuclear extracts from hepatoma cells are assayed for binding to the cAMP response element found in the phosphoenolpyruvate carboxykinase-cytosolic (PEPCK-C) promoter. Although cAMP response element-binding protein and CCAAT/enhancer binding proteins alpha and beta have been identified as liver factors that bind this motif, an uncharacterized, slower migrating complex was also observed. We identify activating transcription factor-2 (ATF-2) as the factor in this complex and show that ATF-2 stimulates expression from the PEPCK-C promoter. ATF-2 is a basic-leucine zipper transcription factor and a target for stress-activated protein kinases. We demonstrate that p38beta mitogen-activated protein (MAP) kinase augments ATF-2 transactivation activity on the PEPCK-C promoter, which is consistent with the interpretation that PEPCK-C promoter activity is maintained under stress through a p38 MAP kinase dependent pathway. In this regard, we show that treatment with sodium arsenite, a known activator of p38 MAP kinases, also stimulates expression from the PEPCK promoter. These results show that ATF-2 can stimulate transcription of the PEPCK-C promoter and support a role for stress inducible kinases in the maintenance of PEPCK-C expression.
Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, Maryland 20852-1727, USA.
J
J
Cheong
J E
JE
Coligan
J D
JD
Shuman
D051698:Activating Transcription Factor 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D017930:Genes, Reporter; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases; D018384:Oxidative Stress; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013379:Substrate Specificity; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014407:Tumor Cells, Cultured
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP)