Global analysis of gene expression identifies C/EBP and TEF-1 as major p38 alpha MAP kinase-regulated transcription factors in proliferating cardiomyocytes.

p38 MAPKs (mitogen-activated protein kinases) play important roles in the regulation of cellular responses to environmental stress. Recently, this signalling pathway has also been implicated in the regulation of processes unrelated to stress, for example, in T lymphocytes and cardiomyocytes. In order to identify molecular targets responsible for the housekeeping functions of p38 MAPKs, we have analysed the differences in the transcriptomes of normally proliferating wild-type and p38α knockout immortalized embryonic cardiomyocytes. Interestingly, many potential components of the myocardium extracellular matrix were found to be upregulated in the absence of p38α. Further analysis of the microarray data identified TEF-1 (transcriptional enhancer factor-1), a known regulator of heart-specific gene expression, and C/EBPβ (CCAAT/enhancer-binding protein β), as the two transcription factors the binding sites ofwhich were most enriched in the promoters of p38α-regulated genes. We have focused on the study of the extracellular matrix component COL1A1 (α1 chain of type I collagen) and found evidence for the involvement of both TEF-1 and C/EBPβ in the p38α-dependent inhibition of COL1A1 transcription. Our data therefore show that p38 MAPKs regulate TEF-1 andC/EBPβ transcriptional activity in the absence of environmental stress and suggests a role for p38α in the expression of extracellular matrix components that maintain organ architecture.