RXR-mediated regulation of the α-fetoprotein gene through an upstream element

Chen Li, Joseph Locker, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Retinoic acid (RA) is known to have potent effects on development and differentiation. RA exerts its effects on transcription through two distinct classes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), that bind to specific RA-responsive elements (RARE) in target genes. α-Fetoprotein (AFP), a hepatocyte differentiation, maturation, and carcinogenesis marker, is transcriptionally upregulated by RA in McA-RH8994 hepatoma cells. Using deletion mapping analysis, we have identified a RARE-like sequence that is located between -2406 and -2378 of the transcription initiation site of the rat AFP gene. Sequence analysis demonstrated that this cis-acting element consists of three direct repeats and one inverted repeat of a GGGTCA-like half-site. The putative RARE can specifically bind to both RXR homodimers and RAR/RXR heterodimers as determined by gel mobility shift assays. A DR1 direct repeat was more efficient than a DR5 direct repeat oligonucleotide in competition for binding of the putative RARE to RXR and RAR/RXR. A mutagenesis study indicated that to have a full-strength induction, all the repeats were required. To further analyze the function of this element in vivo, a reporter gene construct of the putative RARE combined with the thymidine kinase promoter was cotransfected with RAR and RXR expression plasmids in CV1 cells. CAT assays demonstrated that overexpression of RXRα conferred the best RA response, consistent with our previous observation that 9-cis-RA is more potent than all-trans-RA for inducing the expression of the AFP gene. In addition, the RXR selective ligand LG100153 alone can stimulate the expression of the AFP gene. Our data suggest that an RXR-mediated pathway exists for modulation of AFP gene expression through a specific element.

Original languageEnglish (US)
Pages (from-to)955-963
Number of pages9
JournalDNA and Cell Biology
Volume15
Issue number11
StatePublished - 1996

Fingerprint

Fetal Proteins
Retinoid X Receptors
Tretinoin
Retinoic Acid Receptors
Genes
Nucleic Acid Repetitive Sequences
Gene Expression
Thymidine Kinase
Transcription Initiation Site
Electrophoretic Mobility Shift Assay
Cytoplasmic and Nuclear Receptors
Reporter Genes
Oligonucleotides
Mutagenesis
Sequence Analysis
Hepatocytes
Hepatocellular Carcinoma
Carcinogenesis
Plasmids
Gels

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

RXR-mediated regulation of the α-fetoprotein gene through an upstream element. / Li, Chen; Locker, Joseph; Wan, Yu-Jui Yvonne.

In: DNA and Cell Biology, Vol. 15, No. 11, 1996, p. 955-963.

Research output: Contribution to journalArticle

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