The zinc finger transcription factor, MOK2, negatively modulates expression of the interphotoreceptor retinoid-binding protein gene, IRBP

The human and murine MOK2 orthologue genes encode Kruppel/TFIIIA-related zi nc finger proteins, which are factors able to recognize both DNA and RNA th rough their zinc finger motifs, MOK2 proteins have been shown to bind to th e same 18-base pair (bp)-specific sequence in duplex DNA. This MOK2-binding site was found within introns 7 and 2 of human PAX3 and interphotoreceptor retinoid-binding protein (IRBP) genes, respectively. As these two genes ar e expressed in the brain as MOK2, we have suggested that PAX3 and IRBP gene s are two potentially important target genes for the MOK2 protein. In this study, we focused our attention on IRBP as a potential MOK2 target gene. Se quence comparison and binding studies of the 18-bp MOK2-binding sites prese nt in intron 2 of human, bovine, and mouse IRBP genes show that the 3'-half sequence is the essential core element for MOK2 binding. Very interestingl y, 8-bp of this core sequence are found in a reverse orientation, in the IR BP promoter. We demonstrate that MOK2 can bind to the 8-bp sequence present in the IRBP promoter and repress its transcription when transiently overex pressed in retinoblastoma Weri-RB1 cells. In the IRBP promoter, it appears that the TAAAGGCT MOK2-binding site overlaps with the photoreceptor-specifi c CRX-binding element. We suggest that MOK2 represses transcription by comp eting with the cone-rod homeobox protein (CRX) for DNA binding, thereby dec reasing transcriptional activation by CRX. Furthermore, we show that Mok2 e xpression in the developing mouse and in the adult retina seems to be conco rdant with IRBP expression.