title: Calcium and cellular clocks orchestrate cell division.
abstract: The results of experiments recently reported from this and other laboratories provide firm support for Heilbrunn's thesis that mitotic events are initiated by transient elevation of intracellular Ca2+, derived from intracellular stores. The ATP-dependent MA Ca2(+)-pump working in concert with an endomembrane Ca2+ channel appears to share the responsibility for regulating these Ca2+ signals. Further results demonstrated a limited time window during which the cell is sensitive to agents that impose mitotic arrest by interfering with transient elevations in intracellular "free" Ca2+ concentration. From this it appears that a discrete, timed increase in cytosolic Ca2+ derived from endomembrane stores is a necessary signal for regulating the onset of NEB, AO, and mitosis. Results from the arrest and release experiments provide support for a model in which Ca2+ is used to coordinate the action of parallel independent and interdependent biochemical pathways whose interaction results in the cytologic events of mitosis. These pathways apparently are operating under the influence of a metabolic "clock" that continues to cycle, at least once, in the absence of a Ca2+ transient sufficient to initiate NEB or AO. The discrete and temporal regulation of this Ca2+ transient through the interaction of the endomembrane Ca2+ pump, an endomembrane Ca2+ channel, and intracellular Ca2(+)-dependent reaction pathways suggest a mechanism incorporating a negative feedback loop to limit the size and duration of the Ca2+ transient and prevent the release of excessive amounts of Ca2+. Deeper understanding of the regulatory mechanism that governs the onset of mitosis requires: (1) quantitative imaging of intracellular Ca2+, especially the Ca2+ signal throughout the cell cycle, with high spatial and temporal resolution; and (2) identifying the molecules responsible for regulating the expression and reception of the Ca2+ signal itself. It is clear that Ca2(+)-dependent pathways are necessary elements of the mitotic process. Molecular candidates for the regulators and regulatees have yet to be identified. The upstream controlling molecules of these transmembrane Ca2+ regulatory elements, as well as the initial mitotic "start" signal, await future identification. Downstream regulation is also clearly indicated, perhaps through regulation of cyclin expression, degradation, or both.
authors.affiliation: Department of Physiology, Cornell University, Ithaca, New York 14853.
authors.forename: R B
authors.initials: RB
authors.lastname: Silver
mesh_terms: D000818:Animals; D001683:Biological Clocks; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D007425:Intracellular Membranes / Q000502:physiology; D008938:Mitosis / Q000502:physiology
chemical_list: D015220:Calcium Channels; D002118:Calcium