Retinoic acid reduces p11 protein levels in bronchial epithelial cells by a posttranslational mechanism.
p11 is a member of the S100 family of proteins, is the cellular ligand of annexin II, and interacts with the carboxyl region of 85-kDa cytosolic phospholipase A(2) (cPLA(2)), inhibiting cPLA(2) activity and arachidonic acid (AA) release. We studied the effect of retinoic acid (RA) on PLA(2) activity in human bronchial epithelial cells and whether p11 contributes to these effects. The addition of 10(-6) M RA resulted in reduced p11 protein levels at 4 days, with the greatest effect observed on days 6 and 7. This effect was dose related (10(-6) to 10(-9) M). RA treatment (10(-6) M) had no effect on cPLA(2) protein levels. p11 mRNA levels were unchanged at 6 and 8 days of treatment (correlating with maximum p11 protein reduction). Treatment with RA reduced p11 levels in control cells and in cells transfected with a p11 expression vector, suggesting a posttranslational mechanism. Lactacystin (10(-6) M), an inhibitor of the human 26S proteasome, blocked the decrease in p11 observed with RA treatment. Compared with control cells (n = 3), RA-treated cells (n = 3) had significantly increased AA release after treatment with the calcium ionophore A-23187 (P = 0.006). Therefore, RA reduces p11 protein expression and increases PLA(2) activity and AA release.
Gladwin
M T
MT
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. mgladwin@nih.gov
Yao
X L
XL
Cowan
M
M
Huang
X L
XL
Schneider
R
R
Grant
L R
LR
Logun
C
C
Shelhamer
J H
JH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017306:Annexin A2 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D009418:S100 Proteins; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014452:Ubiquitins / Q000378:metabolism; D000099248:S100 Calcium Binding Protein A10
D000111:Acetylcysteine; D017306:Annexin A2; D000970:Antineoplastic Agents; D016718:Arachidonic Acid; D000001:Calcimycin; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D007476:Ionophores; D009097:Multienzyme Complexes; D010455:Peptides; D010741:Phospholipases A; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D009418:S100 Proteins; D014212:Tretinoin; D014452:Ubiquitins; D000099248:S100 Calcium Binding Protein A10; C067713:lactacystin