Attenuation of glucocorticoid functions in an Anx-A1-/- cell line

Biochem J. 2003 May 1;371(Pt 3):927-35. doi: 10.1042/BJ20021856.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexins / genetics
  • Annexins / physiology*
  • Arachidonic Acid / metabolism
  • Cell Cycle
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line
  • Dexamethasone / pharmacology
  • Dinoprostone / metabolism
  • Glucocorticoids / physiology*
  • Indomethacin / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron

Substances

  • Annexins
  • Glucocorticoids
  • Arachidonic Acid
  • Dexamethasone
  • Dinoprostone
  • Indomethacin