Calcium and cellular clocks orchestrate cell division

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.