All-trans retinoic acid down-regulates human albumin gene expression through the induction of C/EBPbeta-LIP.
ATRA (all-trans retinoic acid), which is a major bioactive metabolite of vitamin A and a potent regulator of development and differentiation, mediates down-regulation of the human albumin gene. However, the mechanism of ATRA-mediated down-regulation is not well understood. In the present study, deletion analysis and luciferase assays demonstrate that ATRA causes a marked decrease in the activity of the albumin promoter, the region between nt -367 and -167 from the transcription start site, where C/EBP (CCAAT/enhancer-binding protein)-binding sites are tightly packed, is indispensable for ATRA-mediated down-regulation. ChIP (chromatin immunoprecipitation) assays revealed that in vivo binding of C/EBPalpha to the region markedly decreases upon incubation with ATRA, whereas ATRA treatment marginally increases the recruitment of C/EBPbeta. We found that ATRA has the ability to differentially and directly induce expression of a truncated isoform of C/EBPbeta, which is an LIP (liver-enriched transcriptional inhibitory protein) that lacks a transactivation domain, and to increase the binding activity of C/EBPbeta-LIP to its response element. Overexpression of C/EBPbeta-LIP negatively regulates the endogenous expression of albumin, as well as the activity of the albumin promoter induced by C/EBP transactivators such as C/EBPalpha and full-length C/EBPbeta. In conclusion, we propose a novel model for down-regulation of the albumin gene, in which ATRA triggers an increase in the translation of C/EBPbeta-LIP that antagonizes C/EBP transactivators by interacting with their binding sites in the albumin promoter.
Masaki
Takahiro
T
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Matsuura
Tomokazu
T
Ohkawa
Kiyoshi
K
Miyamura
Tatsuo
T
Okazaki
Isao
I
Watanabe
Tetsu
T
Suzuki
Tetsuro
T
D000418:Albumins / Q000096:biosynthesis* / Q000235:genetics; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015533:Transcriptional Activation; D014212:Tretinoin / Q000502:physiology*
D000418:Albumins; D022782:CCAAT-Enhancer-Binding Protein-beta; D014212:Tretinoin