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.
Rybner
C
C
INSERM U-496, Institut Universitaire d'Hématologie (IUH), Hôpital Saint-Louis, Paris, France.
Hillion
J
J
Sahraoui
T
T
Lanotte
M
M
Botti
J
J
D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000473:pathology; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D018621:PrPC Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D008565:Membrane Proteins; D018621:PrPC Proteins; D012333:RNA, Messenger; D014212:Tretinoin