The two isoforms of protein phosphatase 2A catalytic subunit are expressed at different levels in all tissues and human cell lines analyzed. This differential expression suggests a specific function for the two isoforms. The structures of the C alpha and C beta genes are highly conserved. The most sequence divergence occurs in exon I and in the 3'-nontranslated region of exon VII. These divergent regions are highly conserved between species implying that they serve a specific function in terms of RNA regulation. Both promoter regions show characteristic features of "housekeeping" genes. This correlates well with a basal expression of both mRNAs observed in all cell lines and tissues. However, a differential expression of the two isoforms was observed. Analysis of the promoter activity in transiently transfected HeLa cells indicates that this differential expression is partially due to different promoter activities. It remains an interesting question whether the CRE in the alpha gene provides a mechanism for the transcriptional regulation by the cAMP signal transduction pathway. This would appear to be the first description where a protein kinase can modulate the mRNA levels of a protein phosphatase.