CALCIUM - CELL-CYCLE REGULATOR, DIFFERENTIATOR, KILLER, CHEMOPREVENTOR, AND MAYBE, TUMOR PROMOTER

Ca2+ and Ca2+-binding proteins are involved in running the cell cycle. Ca2+ spikes and signals from integrin-activated focal adhesion comple xes and Ca2+ receptors on the cell surface along with cyclic AMP begin the cycle of cyclin-dependent protein kinases (PKs). These transientl y expressed PKs stimulate the coordinate expression of DNA-replicating enzymes, activate replication enzymes, inactivate replication suppres sors (e.g., retinoblastoma susceptibility protein), activate the repli cator complexes at the end of the G(1) build-up, and when replication is complete they and a Ca2+ spike trigger mitotic prophase Another Ca2 + surge at the end of metaphase triggers the destruction of the propha se-stimulating PKs and starts anaphase. Ca2+ finally stimulates cytopl asmic division (cytokinesis). However, Ca2+ does more than this in epi thelial cells, such as those lining the colon, and skin keratinocytes. These cells also need Ca2+, integrin signals, and only a small amount (e.g., 0.05-0.1 mM) of external Ca2+ to start DNA replication. Signal s from their surface Ca2+ receptors trigger a combination of different iation and apoptosis (''diffpoptosis'') when external Ca2+ concentrati on reaches their set-points. The skin's steep, upwardly directed, Ca2 gradient has a low concentration in the basal layer to allow stem and precursor keratinocytes to proliferate, and higher concentrations in the suprabasal layers to trigger the differentiation-apoptosis (''diff poptosis'') mechanism that converts granular cells into protective, ha rd-shelled, dead corneocytes. A similar Ca2+ gradient may exist in the colon crypt allowing the stem cell and its amplifying transit or prec ursor offspring to cycle in the lower parts of the crypt, while stoppi ng proliferation and stimulating terminal differentiation in the upper crypt and flat mucosa. Raising the amount of Ca2+ in fecal water abov e a critical level reduces proliferation and thus colorectal carcinoge nesis in normal rats and some high-risk humans. But during carcinogene sis the Ca2+ sensors malfunction or their signals become ineffective: high Ca2+ does not stop, and may even stimulate, the proliferation of initiated mutants. Therefore, Ca2+ may either not affect, or even prom ote, the growth of epithelial cells in carcinogen-initiated rat colon and human adenoma patients. Clearly, a much greater understanding of h ow Ca2+ controls the proliferation and differentiation of epithelial c ells and why initiated cells lose their responsiveness to Ca2+ are nee ded to assess the drawbacks and advantages of using Ca2+ as a chemopre ventor. (C) 1995 Wiley-Liss, Inc.