P38 MITOGEN-ACTIVATED PROTEIN-KINASE MEDIATES THE TRANSCRIPTIONAL INDUCTION OF THE ATRIAL-NATRIURETIC-FACTOR GENE THROUGH A SERUM RESPONSE ELEMENT - A POTENTIAL ROLE FOR THE TRANSCRIPTION FACTOR ATF6

In various cell types certain stresses can stimulate p38 mitogen-activ ated protein kinase (p38 MAPK), leading to the transcriptional activat ion of genes that contribute to appropriate compensatory responses, In this report the mechanism of p38-activated transcription was studied in cardiac myocytes where this MAPK is a key regulator of the cell gro wth and the cardiac-specific gene induction that occurs in response to potentially stressful stimuli. In the cardiac atrial natriuretic fact or (ANF) gene, a promoter-proximal serum response element (SRE), which binds serum response factor (SRF), was shown to be critical for ANF i nduction in primary cardiac myocytes transfected with the selective p3 8 MAPK activator, MKK6 (Glu). This ANF SRE does not possess sequences typically required for the binding of the Ets-related ternary complex factors (TCFs), such as Elk-l, indicating that p38-mediated induction through this element may take place independently of such TCFs. Althou gh p38 did not phosphorylate SRF in vitro, it efficiently phosphorylat ed ATF6, a newly discovered SRF-binding protein that is believed to se rve as a coactivator of SRF-inducible transcription at SREs, Expressio n of an ATF6 antisense RNA blocked p38-mediated ANF induction through the ANF SRE. Moreover, when fused to the Gal4 DNA-binding domain, an N -terminal 273-amino acid fragment of ATF6 was sufficient to support tr ans-activation of Gal4/luciferase expression in response to p38 but no t the other stress kinase, N-terminal Jun kinase (JNK); p38-activating cardiac growth promoters also stimulated ATF6 trans-activation. These results indicate that through ATF6, p38 can augment SRE-mediated tran scription independently of Ets-related TCFs, representing a novel mech anism of SRF-dependent transcription by MAP kinases.