Cyclosporin A regulates the levels of cyclophilin A in neuroblastoma cells in culture.
Cyclophilin A (CyP-A), a member of a highly conserved family of proteins, immunophilins, is the major intracellular receptor for the immunosuppressive drug, cyclosporin A (CsA). CyP-A is widely expressed in many tissues, but is found in the highest concentration in brain tissues and may perform critical neuronal functions. CsA is a known neurotoxin. Therefore, understanding the regulation of CyP-A levels in nerve cells, particularly by CsA, is important. We have utilized murine neuroblastoma (NB) cells as an experimental model to investigate this issue. Our results show that CsA alone was sufficient to induce morphological differentiation in undifferentiated NB cells and to increase CyP-A levels as determined by immunostaining. However, inducing terminal differentiation by elevating adenosine 3',5'-cyclic monophosphate (cAMP) levels using either 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO20-1724), an inhibitor of cyclic nucleotide phosphodiesterase, or prostaglandin E1 (PGE1), a stimulator of adenylate cyclase, was not sufficient to increase CyP-A levels. CsA was required to increase CyP-A levels in both RO20-1724- and PGE1-induced differentiated NB cells. Increases in CyP-A levels, however, occurred without any change in the expression of the CyP-A gene as determined by reverse-transcriptase polymerase-chain reaction analysis using (CyP-A)-specific primers. These results suggest that CsA regulates the level of its own binding protein, CyP-A, in both undifferentiated and cAMP-induced differentiated NB cells in culture.
Hovland
A R
AR
Center for Vitamins and Cancer Research, Department of Radiology, University of Colorado Health Sciences Center, Denver 80262, USA.
La Rosa
F G
FG
Hovland
P G
PG
Cole
W C
WC
Kumar
A
A
Prasad
J E
JE
Prasad
K N
KN
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D016572:Cyclosporine; D000242:Cyclic AMP; D019696:Peptidylprolyl Isomerase; D000527:Alprostadil