A DIFFERENT COMBINATION OF TRANSCRIPTION FACTORS MODULATES THE EXPRESSION OF THE HUMAN TRANSFERRIN PROMOTER IN LIVER AND SERTOLI CELLS

We have previously identified the functional regions involved in the r egulation of human transferrin (Tf) gene expression in the liver and i n Sertoli cells of the testis. Here, we show that a different cellular distribution of transcription factors, interacting with the same prox imal promoter regions (PRI and PRII), modulates cell type-specific tra nscription. In the liver, hepatocyte nuclear factor 4 (HNF-4) and the chicken ovalbumin upstream promoter transcription factor (COUP-TF) act at the PRI site, while CCAAT/enhancer-binding proteins (C/EBPs) act a t the PRII site. In the testis, distinct combinations of Sertoli prote ins SP-A and SP-D and COUP-TF bind to the PRI site, while SP-alpha and SP-beta bind to the PRII site. Cotransfection experiments in Hep3B ce lls revealed that mostly HNF-4, C/EBP-alpha, C/EBP-delta, and, to a le sser extent, COUP-TF stimulated transcription driven by the -125/+39 r egion. In Sertoli cells, HNF-4 and COUP-TF appeared to repress, while the C/EBP factors were able to stimulate transcription driven by the - 100/+39 region. However, the specific activating combination remains t o be defined among the Sertoli proteins. In the non-Tf-expressing HeLa cells, the Tf promoter could be activated by C/EBP-delta. Our data re vealed functional antagonism between HF-4 and COUP-TF, binding to PRI, as well as cross-coupling interactions between HNF-4 and C/EBP, bindi ng to adjacent sites. Thus, cell type-specific DNA-protein interaction s, together with protein-protein interactions, may explain the transcr iptional regulation of the Tf gene in different cell types.