Extracellular nucleotides acting through specific P2 receptors activate intracellular signaling cascades. Consistent with the expression of G protein-coupled P2Y receptors in skeletal tissue, the human osteosarcoma cell line SaOS-2 and primary osteoblasts express P2Y(1) and P2Y(2) receptors, respectively. Their activation by nucleotide agonists (ADP and ATP for P2Y(1); ATP and UTP for P2Y(2)) elevates [Ca2+](i) and moderately induces expression of the c-fos proto-oncogene. A synergistic effect on c-fos induction is observed by combining ATP and parathyroid hormone, a key bone cell regulator. Parathyroid hormone elevates intracellular cAMP levels and correspondingly activates a stably integrated reporter gene driven by the Ca2+/cAMP-responsive element of the human c-fos promoter. Nucleotides have little effect on either cAMP levels or this reporter, instead activating luciferase controlled by the full c-fos promoter. This induction is reproduced by a stably integrated serum response element reporter independently of mitogen-activated protein kinase activation and ternary complex factor phosphorylation. This novel example of synergy between the cAMP-dependent protein kinase/CaCRE signaling module and a non-mitogen-activated protein kinase/ternary complex factor pathway that targets the serum response element shows that extracellular ATP, via P2Y receptors, can potentiate strong responses to ubiquitous growth and differentiative factors.
Signaling in human osteoblasts by extracellular nucleotides – Their weak induction of the c-fos proto-oncogene via Ca2+ mobilization is strongly potentiated by a parathyroid hormone/cAMP-dependent protein kinase pathway independently of mitogen-activated protein kinase
Bowler, W. B.; Dixon, C. J.; Halleux, C.; Maier, R.; Bilbe, G.; Fraser, W. D.; Gallagher, J. A.; Hipskind, R. A.
Journal of Biological Chemistry
1999-05-14 / vol 274 / pages 14315-14324
in-vivo; map kinase; growth-factor; atp; calcium influx; gene-transcription; osteosarcoma cells; purinergic receptors; serum response factor; smooth-muscle cells