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-activated protein kinase (p38 MAPK), leading to the transcriptional activation 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 growth and the cardiac-specific gene induction that occurs in response to potentially stressful stimuli. In the cardiac atrial natriuretic factor (ANF) gene, a promoter-proximal serum response element (SRE), which binds serum response factor (SRF), was shown to be critical for ANF induction in primary cardiac myocytes transfected with the selective p38 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-1, indicating that p38-mediated induction through this element may take place independently of such TCFs. Although p38 did not phosphorylate SRF in vitro, it efficiently phosphorylated ATF6, a newly discovered SRF-binding protein that is believed to serve as a co-activator of SRF-inducible transcription at SREs. Expression 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 trans-activation of Gal4/luciferase expression in response to p38 but not 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 transcription independently of Ets-related TCFs, representing a novel mechanism of SRF-dependent transcription by MAP kinases.
Thuerauf
D J
DJ
Department of Biology and Molecular Biology, Institute, San Diego State University, San Diego, California 92182, USA.
Arnold
N D
ND
Zechner
D
D
Hanford
D S
DS
DeMartin
K M
KM
McDonough
P M
PM
Prywes
R
R
Glembotski
C C
CC
D051702:Activating Transcription Factor 6; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000201:enzymology*; D009687:Nuclear Proteins / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016372:RNA, Antisense / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D026362:Serum Response Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D051702:Activating Transcription Factor 6; C497113:Atf6 protein, rat; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D009687:Nuclear Proteins; D016372:RNA, Antisense; D011993:Recombinant Fusion Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases