ROR? phosphorylation by casein kinase 1? as glucose signal to regulate estrogen sulfation in human liver cells.

ABSTRACT: Estrogen sulfotransferase (SULT1E1) metabolically inactivates estrogen and SULT1E1 expression is tightly regulated by multiple nuclear receptors. Human fetal, but not adult, livers express appreciable amounts of SULT1E1 protein, which is mimicked in human hepatoma-derived HepG2 cells cultured in high glucose (450?mg/dl) medium. Here, we have investigated this glucose signal that leads to phosphorylation of nuclear receptor ROR? (NR1F1) at Ser100 and the transcription mechanism by which phosphorylated ROR? transduces this signal to nuclear receptor HNF4?, activating the SULT1E1 promoter. The promoter is repressed by non-phosphorylated ROR? which binds a distal enhancer (-943/-922?bp) and interacts with and represses HNF4?-mediated transcription. In response to high glucose, ROR? becomes phosphorylated at Ser100 and reverses its repression of HNF4? promoter activation. Moreover, the casein kinase CK1?, which is identified in an enhancer-bound nuclear protein complex, phosphorylates Ser100 in in vitro kinase assays. During these dynamic processes, both ROR? and HNF4? remain on the enhancer. Thus, ROR? utilizes phosphorylation to integrate HNF4? and transduces the glucose signal to regulate the SULT1E1 gene in HepG2 cells and this phosphorylation-mediated mechanism may also regulate SULT1E1 expressions in the human liver.

SUBMITTER: Hu H 

PROVIDER: S-EPMC7527261 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature