THE TISSUE-SPECIFIC EXTINGUISHER LOCUS TSE1 ENCODES A REGULATORY SUBUNIT OF CAMP-DEPENDENT PROTEIN-KINASE

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.