Isolation and Functional Analysis of a Keratinocyte-Derived, Ligand-Regulated Nuclear Receptor Comodulator

Keratinocyte (KC) gene expression is regulated by members of the nuclear receptor (NR) superfamily including retinoic acid receptors, retinoid X receptors (RAR and RXR, respectively), and peroxisome proliferator activated receptors (PPAR). In addition to ligand, NR transcriptional activity is controlled by interaction with proteins, collectively known as coregulators, which function as corepressors or coactivators. To improve our understanding of coregulators expressed in epidermis, we screened a KC cDNA library for PPARα-interacting proteins. The screen yielded previously unknown proteins including one we named COPR1, for comodulator of PPAR and RXR. COPR1 and its longer variant COPR2 target the AF-2 domains of NR but exhibit quantitative differences in their functional interactions with RAR, RXRα and PPAR. They decrease but do not completely repress the activity of RXRα and PPARα because of a proline-acid-rich autonomous activation domain. An NR box motif contributes to but is not solely responsible for functional and physical association with RXRα. The activation domain, their relatively small size (COPR1, 26.9 kDa; COPR2, 32.4 kDa), and strict dependence on AF-2 for interaction distinguish COPR1 and COPR2 from the SMRT/NCoR type of corepressor and may represent a means of control that dampens rather than completely represses NR-mediated gene expression