All-trans retinoic acid down-regulates prion protein expression independently of granulocyte maturation

The cellular prion protein (PrPc) is a sialoglycoprotein involved in the pathogenesis of prion diseases. It has been identified at the plasma membrane of several cell types. All-trans retinoic acid (ATRA) is known to induce differentiation of human leukemia cell lines in vitro. PrPc messenger ribonucleic acid (mRNA) and protein are down-regulated upon ATRA-induced differentiation of HL60 cells. In this report, we have investigated the regulation of PrPc mRNA and protein expression during ATRA-treatment of maturation-sensitive (NB4) and -resistant (NB4-R1 and NB4-R2) cell lines. In ATRA-induced maturation of NB4 cells, down-regulation of PrPc mRNA and protein were observed. We also show that down-regulation of PrPc mRNA is dependent on protein synthesis. Moreover, the same down-regulation of prion protein by ATRA was observed at the surface of maturation-resistant, ATRA-responsive NB4-R1 cells. In contrast, the maturation-resistant and ATRA-unresponsive NB4-R2 subline showed no variation in membrane prion protein expression. These results demonstrate a dissociation between the regulation of prion protein expression by ATRA and the process of granulocyte maturation. We propose that retinoids should be investigated further as a preventive strategy to slow down prion disease progression.