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Calcium, cyclic AMP and protein kinase C--partners in mitogenesis
Abstract:
Evidence is steadily mounting that the proto-oncogenes, whose products organize and start the programs that drive normal eukaryotic cells through their chromosome replication/mitosis cycles, are transiently stimulated by sequential signals from a multi-purpose, receptor-operated mechanism (consisting of internal surges of Ca2+ and bursts of protein kinase C activity resulting from phosphatidylinositol 4,5-bisphosphate breakdown and the opening of membrane Ca2+ channels induced by receptor-associated tyrosine-protein kinase activity) and bursts of cyclic AMP-dependent kinase activity. The bypassing or subversion of the receptor-operated Ca2+/phospholipid breakdown/protein kinase C signalling mechanism is probably the basis of the freeing of cell proliferation from external controls that characterizes all neoplastic transformations.
Insights
Proto-oncogenes regulate cell cycles via Ca2+ and kinase signaling. Disrupting this pathway, particularly calcium and protein kinase C, may drive uncontrolled cell proliferation in cancer.
Area of Science:
- Cell biology
- Molecular oncology
- Signal transduction
Background:
- Proto-oncogenes control eukaryotic cell cycle progression.
- Normal cell proliferation is regulated by external signals.
- Cancer involves the loss of this external control.
Purpose of the Study:
- To elucidate the signaling pathways regulating proto-oncogenes.
- To identify the mechanisms underlying uncontrolled cell proliferation in neoplastic transformations.
Main Methods:
- Investigated receptor-operated signaling mechanisms.
- Analyzed the roles of Ca2+ surges and protein kinase C activity.
- Examined the involvement of cyclic AMP-dependent kinase activity.
Main Results:
- Proto-oncogenes are transiently stimulated by sequential signals.
- These signals involve Ca2+ surges and protein kinase C bursts.
- Cyclic AMP-dependent kinase activity also plays a role.
Conclusions:
- The Ca2+/phospholipid breakdown/protein kinase C pathway is crucial for cell cycle regulation.
- Bypassing or subverting this pathway leads to uncontrolled cell proliferation.
- This disruption is fundamental to neoplastic transformations.