The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase

Abstract

The tissue-specific extinguisher locus TSE1, a dominant negative regulator of transcription in somatic cell hybrids, acts via a cAMP response element (CRE) to repress activity of a hepatocyte-specific enhancer. Guided by the antagonism between TSE1 and cAMP-mediated signal transduction, we identified the regulatory subunit RI alpha of protein kinase A (PKA) as the product of the TSE1 locus. The evidence derives from concordant expression of RI alpha mRNA and TSE1 genetic activity, high resolution mapping of the RI alpha gene and TSE1 on human chromosome 17, and the ability of a transfected RI alpha cDNA to generate a phenocopy of TSE1-mediated extinction. The mechanism of TSE1/RI alpha-mediated extinction involves repression of basal PKA activity, reduced phosphorylation of CREB at Ser-133, and a corresponding reduction of in vivo protein binding at the target CRE.