FUNCTIONAL INTERACTIONS BETWEEN NUCLEAR RECEPTORS RECOGNIZING A COMMON SEQUENCE ELEMENT, THE DIRECT REPEAT MOTIF SPACED BY ONE NUCLEOTIDE (DR-1)

Direct repeat motifs composed of two hexamer half-sites spaced by a si ngle nucleotide (DR-1) are recognized by several members of the nuclea r hormone receptor superfamily. We examined, by means of gene transfec tion assays, the interplay between the DR-1-binding nuclear receptors commonly expressed in liver, peroxisome proliferator-activated recepto r alpha (PPAR alpha), hepatocyte nuclear factor-4 (HNF-4), and chicken ovalbumin upstream transcription factor I (COUP-TFI). Both PPAR alpha and HNF-4 efficiently bound to the acyl-CoA oxidase gene enhancer ele ment, but PPAR alpha exhibited much stronger transactivation than HNF- 4, As a result, HNF-4 suppressed the gene-activating function of PPAR alpha, when they were expressed together, due to competition for a com mon binding site. On the other hand, HNF-4, but not PPAR alpha, effect ively bound to the apolipoprotein CIII gene element, and activated gen e transcription. PPAR alpha had no effect even when co-expressed with HNF-4, COUP-TFI bound to both elements, and suppressed the gene activa tion by PPAR alpha and HNF-4. Thus, these nuclear receptors have indiv idual functions in gene regulation, and exhibit complex compound effec ts when they co-exist.