Peptidyl-prolyl isomerases (PPIase) facilitate the cis-trans interconversion of the peptidyl-prolyl bond and in such way affect protein folding. Pin1 is a PPIase, which specifically recognizes phosphorylated S/T-P bonds. The transcription factor TFIIH mediates phosphorylation of the retinoic, acid receptor alpha (RARalpha) at position Ser(77). In the presence of retinoic acid ligand (RA), the Ser(77) non-phosphorylated receptor is suggested to undergo degradation through the proteasome pathway. Here we provide evidence that Pin1 is able to selectively destabilize RARalpha in a ligand independent-manner. We show that this is caused by RARalpha ubiquitination, which in turn is phosphorylation dependent. The single mutation Ser(77)>A completely abolishes RARalpha degradation whereas the mutation Ser(77)>E rescues this effect. In addition, we correlate RARalpha stability to Ser(77) phosphorylation required for the ligand independent transcriptional activity on fgf8 promoter. Finally, we show that the ligand-independent Ser(77) phosphorylation requires the genuine ligand-binding domain. (C) 2004 Elsevier Inc. All rights reserved.