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Calcium—cell cycle regulator, differetiator, killer, chemopreventor, and maybe, tumor promoter
Author(s) -
Whitfield James F.,
Bird Ranjana P.,
Chakravarthy Balu R.,
Isaacs Richard J.,
Morley Paul
Publication year - 1995
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240590811
Subject(s) - microbiology and biotechnology , cell cycle , biology , mitosis , cytokinesis , focal adhesion , signal transduction , cell division , cell , biochemistry
Ca 2+ and Ca 2+ ‐binding proteins are involved in running the cell cycle. Ca 2+ spikes and signals from integrin‐activated focal adhesion complexes and Ca 2+ receptors on the cell surface along with cyclic AMP begin the cycle of cyclin‐dependent protein kinases (PKs). These transiently expressed PKs stimulate the coordinate expression of DNA‐replicating enzymes, activate replication enzymes, inactivate replication suppressors ( e.g. , retinoblastoma susceptibility protein), activate the replicator complexes at the end of the G 1 build‐up, and when replication is complete they and a Ca 2+ spike trigger mitotic prophase. Another Ca 2+ surge at the end of metaphase triggers the destruction of the prophase‐stimulating PKs and starts anaphase. Ca 2+ finally stimulates cytoplasmic division (cytokinesis). However, Ca 2+ does more than this in epithelial cells, such as those lining the colon, and skin keratinocytes. These cells also need Ca 2+ , integrin signals, and only a small amount (e.g., 0.05–0.1 mM) of external Ca 2+ to start DNA replication. Signal from their surface Ca 2+ receptors trigger a combination of differentiation and apoptosis (“diffpoptosis”) when external Ca 2+ concentration reaches their setpoints. The skin's steep, upwardly directed, Ca 2+ 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 (“diffpoptosis”) mechanism that converts granular cells into protective, hard‐shelled, dead corneocytes. A similar Ca 2+ gradient may exist in the colon crypt allowing the stem cell and its amplifying transit or precursor offspring to cycle in the lower parts of the crypt, while stopping proliferation and stimulating terminal differentiation in the upper crypt and flat mucosa. Raising the amount of Ca 2+ in fecal water above a critical level reduces proliferation and thus colorectal carcinogenesis in normal rats and some high‐risk humans. But during carcinogenesis the Ca 2+ sensors malfunction or their signals become ineffective: high Ca 2+ does not stop, and may even stimulate, the proliferation of initiated mutants. Therefore, Ca 2+ may either not affect, or even promote, the growth of epithelial cells in carcinogen‐initiated rat colon and human adenoma patients. Clearly, a much greater understanding og how Ca 2+ controls the proliferation and differentiation of epithelial cells and why initiated cells lose their reponsiveness to Ca 2+ are needed to asses the drawbacks and advatages of using Ca 2+ as a chemopreventor.