Regulation of Cell Cycle Progression by Calcium/Calmodulin-Dependent Pathways

Abstract

Many hormones, growth factors, and cytokines regulate proliferation of their target cells. Perhaps the most universal signaling cascades required for proliferative responses are those initiated by transient rises in intracellular calcium (Ca2+). The major intracellular receptor for Ca2+ is calmodulin (CaM). CaM is a small protein that contains four EF-hand Ca 2+ binding sites and is highly conserved among eukaryotes. In all organisms in which the CaM gene has been deleted, it is essential. Although Ca2+/CaM is required for proliferation in both unicellular and multicellular eukaryotes, the essential targets of Ca2+/CaM- dependent pathways required for cell proliferation remain elusive. Potential Ca2+/CaM-dependent targets include the serine/threonine phosphatase calcineurin and the family of multifunctional Ca2+/CaM-dependent protein kinases. Whereas these enzymes are essential in Aspergillus nidulans, they are not required under normal growth conditions in yeast. However, in mammalian cells, studies demonstrate that both types of enzymes contribute to the regulation of cell cycle progression. Unfortunately, the mechanism by which Ca2+/CaM and its downstream targets, particularly calcineurin and the Ca2+/CaM-dependent protein kinases, regulate key cell cycle-regulatory proteins, remains enigmatic. By understanding how Ca 2+/CaM regulates cell cycle progression in normal mammalian cells, we may gain insight into how hormones control cell division and how cancer cells subvert the need for Ca2+ and its downstream targets to proliferate.