Attenuation of glucocorticoid functions in an Anx-A1-/- cell line.
The Ca(2+)- and phospholipid-binding protein Anx-A1 (annexin 1; lipocortin 1) has been described both as an inhibitor of phospholipase A(2) (PLA(2)) activity and as a mediator of glucocorticoid-regulated cell growth and eicosanoid generation. Here we show that, when compared with Anx-A1(+/+) cells, lung fibroblast cell lines derived from the Anx-A1(-/-) mouse exhibit an altered morphology characterized by a spindle-shaped appearance and an accumulation of intracellular organelles. Unlike their wild-type counterparts, Anx-A1(-/-) cells also overexpress cyclo-oxygenase 2 (COX 2), cytosolic PLA(2) and secretory PLA(2) and in response to fetal calf serum, exhibit an exaggerated release of eicosanoids, which is insensitive to dexamethasone (10(-8)- 10(-6) M) inhibition. Proliferation and serum-induced progression of Anx-A1(+/+) cells from G(0)/G(1) into S phase, and the associated expression of extracellular signal-regulated kinase 2 (ERK2), cyclin-dependent kinase 4 (cdk4) and COX 2, is strongly inhibited by dexamethasone, whereas Anx-A1(-/-) cells are refractory to the drug. Loss of the response to dexamethasone in Anx-A1(-/-) cells occurs against a background of no apparent change in glucocorticoid receptor expression or sensitivity to non-steroidal anti-inflammatory drugs. Taken together, these observations suggest strongly that Anx-A1 functions as an inhibitor of signal-transduction pathways that lead to cell proliferation and may help to explain how glucocorticoids regulate these processes.
Croxtall
Jamie D
JD
Department of Biochemical Pharmacology, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK. J.Croxtall@qmul.ac.uk
Gilroy
Derek W
DW
Solito
Egle
E
Choudhury
Qamrul
Q
Ward
Barbara J
BJ
Buckingham
Julia C
JC
Flower
Rod J
RJ
D000818:Animals; D017302:Annexins / Q000235:genetics / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005938:Glucocorticoids / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron
D017302:Annexins; D005938:Glucocorticoids; D016718:Arachidonic Acid; D003907:Dexamethasone; D015232:Dinoprostone; D007213:Indomethacin