MODULATION OF RETINOIC ACID SENSITIVITY IN LUNG-CANCER CELLS THROUGH DYNAMIC BALANCE OF ORPHAN RECEPTORS NUR77 AND COUP-TF AND THEIR HETERODIMERIZATION

The diverse function of retinoic acid (RA) is mediated by its nuclear receptors, the retinoic acid receptors (RARs) and retinoid,X receptors (RXRs), However, the RA response is often lost in cancer cells that e xpress the receptors, Previously, it was demonstrated that the RA resp onse is regulated by the COUP-TF orphan receptors, Here, we present ev idence that nur77, another orphan receptor whose expression is highly induced by phorbol esters and growth factors, is involved in modulatio n of the RA response, Expression of nur77 enhances ligand-independent transactivation of RA response elements (RAREs) and desensitizes their RA responsiveness. Conversely,;expression of COUP-TF sensitizes RA re sponsiveness of RAREs by repressing their basal transactivation activi ty;, Unlike the effect of COUP-TFs, the function of nur77 does not req uire direct binding of nur77 to the RAREs, but is through interaction between nur77 and COUP-TFs, The interaction occurs in solution and res ults in inhibition of COUP-TF RARE binding and transcriptional activit y, Unlike other nuclear receptors, a large portion of the carboxy-term inal end of nur77 is not required for its interaction with COUP-TF: In human lung cancer cell lines, COUP-TF is highly expressed in RA-sensi tive cell lines while nur77 expression is associated with RA resistanc e, Stable expression of COUP-TF in nur77-positive, RA-resistant lung c ancer cells enhances the inducibility of RAR beta gene expression and growth inhibition by RA, These observations demonstrate that a dynamic equilibrium between orphan receptors nur77 and COUP-TF, through their heterodimerization that regulates COUP-TF RARE binding, is critical f or RA responsiveness of human lung cancer cells.