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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 4, April, 2002 506-515

Cell Cycle Regulation of Pulmonary Phosphatidylcholine Synthesis

Irene Tseu, Ross Ridsdale, Jason Liu, Jinxia Wang, and Martin Post

CIHR Group in Lung Development and the Lung Biology Programme, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; and Department of Pediatrics, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

Pulmonary surfactant phosphatidylcholine (PC) formation increases as alveolar type II cells mature and arrest in G0/G1 state of the cell cycle at late fetal gestation. To determine whether this G0/G1 arrest is responsible for the increase in PC synthesis, we investigated the rates of PC synthesis and the activity, phosphorylation, intracellular distribution, synthesis, and degradation of a key enzyme of PC synthesis, cytidine triphosphate (CTP):phosphocholine cytidylyltransferase (CCTalpha ). In synchronized mouse lung epithelial (MLE)-15 cells, PC production and CCTalpha activity peaked at G0/G1, declined during transition to G1/S, and remained low during S and G2/M. The changes in CCTalpha activity were not due to alterations in CCTalpha gene and protein expression. CCTalpha protein degradation also did not change during the cell cycle. Indirect immunofluorescence and immunogold electron microscopy revealed that CCTalpha localized to the cytoplasmic compartment and that its cytosolic localization did not change with the cell cycle. Although immunoblotting suggested no major redistribution of CCTalpha mass from cytosol to endoplasmic reticulum, activity measurements revealed that the ratio of particulate/soluble CCTalpha activity was cell cycle-dependent. The particulate/soluble ratio peaked at G0/G1 and declined with cell-cycle progression. Furthermore, the decrease in CCTalpha activity during exit from G0/G1 was associated with an increase in CCTalpha phosphorylation. These data suggest that the cell-cycle changes in PC synthesis are likely not due to alterations in CCTalpha expression and degradation but are primarily a consequence of changes in CCTalpha activity, phosphorylation, and membrane affinity.

Abbreviations: bovine serum albumin, BSA; CTP:phosphocholine cytidylyltransferase, CCT; 4',6-diamidino-2-phenylindole, DAPI; enhanced chemiluminescence, ECL; endoplasmic reticulum, ER; fluorescent-activated cell sorter, FACS; fetal bovine serum, FBS; fetal calf serum, FCS; fluoroisothiocyanate, FITC; green fluorescence protein, GFP; mouse lung epithelial; HA, haemagglutinin; Ham's F12, insulin, transferin, beta  estradiol, and sodium selenite, HITES; immunoglobulin G, IgG; Eagle's minimum essential medium, MEM; mouse lung epithelial, MLE; normal goat serum, NGS; phosphate-buffered saline, PBS; phosphatidylcholine, PC; respiratory distress syndrome RDS; reverse transcriptase/polymerase chain reaction, RT-PCR; SDS-polyacrylamide gel electrophoresis, SDS-PAGE.




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