Boshart M, Weih F, Nichols M, Schütz G
Institute of Cell and Tumor Biology, German Cancer Research Center, Heidelberg.
Cell. 1991 Sep 6;66(5):849-59. doi: 10.1016/0092-8674(91)90432-x.
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.
组织特异性消除基因座TSE1是体细胞杂种中转录的显性负调控因子，它通过环磷酸腺苷反应元件（CRE）发挥作用，抑制肝细胞特异性增强子的活性。在TSE1与环磷酸腺苷介导的信号转导之间的拮抗作用的指导下，我们确定蛋白激酶A（PKA）的调节亚基RIα是TSE1基因座的产物。证据来自RIα mRNA与TSE1遗传活性的一致表达、RIα基因和TSE1在人类17号染色体上的高分辨率定位，以及转染的RIα cDNA产生TSE1介导的消除表型模拟的能力。TSE1/RIα介导的消除机制涉及基础PKA活性的抑制、CREB在Ser-133处磷酸化的减少以及体内靶标CRE处蛋白质结合的相应减少。
