Oncogenes, ions, and phospholipids.
Recent discoveries in tumor virology, lipid biochemistry, and ion transport studies promise to revolutionize our understanding of cell proliferation, differentiation, and tumorigenesis. A model is proposed, based on similar schemes presented recently by others, that incorporates these discoveries and provides a focus for future research on the functions of oncogene proteins. The model suggests that the early (competence) events in the initiation of cell proliferation are triggered by activation of phosphatidylinositol (PI) turnover, which releases two second messengers, 1,2-diacylglycerol (1,2-DG) and inositol-1,4,5-trisphosphate (IP3). PI turnover is proposed to be regulated by the oncogene protein kinases (src, ros, abl, fps) either directly (acting as PI kinases) or indirectly (as tyrosine kinases). The IP3 triggers Ca2+ release from internal stores, and the elevation of cytosolic Ca2+ acts synergistically with 1,2-DG to activate the Ca2+- and phospholipid-dependent kinase C. Kinase C copurifies with the receptor for the tumor-promoting phorbol esters. It is suggested that kinase C then activates the Na+-H+ exchange system, resulting in an elevation of cytosolic pH and Na+, and that these ionic signals (including the change in Ca2+), either in concert or individually, induce further events, including expression of the protooncogene c-myc, which together commit the cell to initiate replication. Evidences in support of this model are reviewed, together with complications indicating its present inadequacies, particularly recent data suggesting that 1,2-DG may activate tyrosine kinases independent of kinase C.
Macara
I G
IG
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology*; D008563:Membrane Lipids / Q000502:physiology*; D051379:Mice; D008934:Mitogens; D009363:Neoplasm Proteins / Q000235:genetics; D009857:Oncogenes; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014158:Transcription, Genetic
D007295:Inositol Phosphates; D007473:Ion Channels; D008563:Membrane Lipids; D008934:Mitogens; D009363:Neoplasm Proteins; D010716:Phosphatidylinositols; D010743:Phospholipids; D015544:Inositol 1,4,5-Trisphosphate; D011494:Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase