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


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.



in-vivo; map kinase; growth-factor; atp; calcium influx; gene-transcription; osteosarcoma cells; purinergic receptors; serum response factor; smooth-muscle cells

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