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 extra cts from hepatoma cells are assayed for binding to the cAMP response e lement 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 Live r factors that bind this motif, an uncharacterized, slower migrating c omplex was also observed. We identify activating transcription factor- 2 (ATF-2) as the factor in this complex and show that ATF-S stimulates expression from the PEPCK-C promoter. ATF-2 is a basic-leucine zipper transcription factor and a target for stress-activated protein kinase s. We demonstrate that p38 beta mitogen-activated protein (MAP) kinase augments ATF-S transactivation activity on the PEPCK-C promoter, whic h 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 PEP CK promoter. These results show that ATF-2 can stimulate transcription of the PEPCK-C promoter and support a role for stress inducible kinas es in the maintenance of PEPCK-C expression.