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.
Boshart
M
M
Institute of Cell and Tumor Biology, German Cancer Research Center, Heidelberg.
Weih
F
F
Nichols
M
M
Schütz
G
G
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D017362:Cyclic AMP Response Element-Binding Protein; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008114:Liver Neoplasms, Experimental; D008969:Molecular Sequence Data; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011953:Receptors, Cyclic AMP / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction
D017362:Cyclic AMP Response Element-Binding Protein; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D004268:DNA-Binding Proteins; C517834:PRKAR1A protein, human; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D011953:Receptors, Cyclic AMP; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases