Calmodulin and Cell Proliferation

As stated earlier, among the targets of CaM are the cytoskeletal proteins MAP-2 and the tau protein. The conclusion is inescapable, therefore, that CaM might be involved in cytoskeletal reorganisation. Both cell proliferation and cell motility have been regarded as the natural foci of CaM involvement. CaM seems to be actively associated with cell proliferation, as amply demonstrated by several investigators. Indeed, it is regarded as an essential ingredient of cell proliferation and the progression of the cell cycle (Means, 1994). The exit of cells from the cell cycle has been reported to be accompanied by a decrease in CaM levels (Christenson and Means, 1993). CaM levels increase as cells progress into the mitotic phase, and there is an elegant demonstration that both Ca2+ and CaM are essential for this process. When either of these is reduced cells undergo G2 arrest (K.P. Lu et al. 1993).

Some investigators have examined the levels of CaM expression in relation to growth responses. Exaggerated growth responses have been recorded in cardiomyo-cytes resulting from an overexpression of CaM (Gruver et al. 1993). Recently, however, Prostko et al. (1997) found no effects on growth responses arising from an overexpression of CaM in C6 glioma cells in culture, but reduction of CaM expression was found to inhibit their growth. The antiproliferative effects exerted by CaM inhibitors have also provided a substantial body of evidence that suggests an association of CaM with growth responses. Several CaM inhibitors have been tested to date. Schuller et al. (1991) found that B859-35, which is a dihydropyridine derivative, markedly inhibited proliferation of three human lung cancer cell lines. Hait et al. (1994) reported that several phenothiazine antipsychotic drugs inhibit CaM and also the proliferation of C6 glioma cells. They also found that the antiproliferative effects corresponded with the inhibition of CaM-sensitive phosphodiesterases. Further work from the same laboratory has shown that KS-501 and KS-502 similarly affect cell proliferation, not by direct action on the enzymes but by interfering with their function of activating CaM (Hait et al. 1995). In other words, the failure to activate CaM appears to lead to an inhibition of cell proliferation. Glass-Marmor et al. (1996) and Glass-Marmor and Beitner (1997) have investigated the effects of another class of CaM inhibitors, which reduce intracellular levels of glucose 1,6-bisphosphate, fructose 1,6-bisphosphate, and ATP and also detach glycolytic enzymes bound to the cytoskeleton. Four antagonists tested — thioridazine, CGS 9343B, clotrimazole, and bifonazole — brought about a marked reduction in cell viability (Glass-Marmor et al. 1996). The detachment of glycolytic enzymes associated with the cytoskeleton can also affect the function of the latter in cytokinesis.

CaM cDNA has been transfected in sense as well as in the antisense orientation into C6 glioma cells. Transfection with sense-cDNA has been found to produce more clones than transfection with antisense constructs. The DNA content of cells has been reported to correlate with CaM levels (Liu G.X. et al. 1996). This is compatible with the finding that cells experience a delay in DNA synthesis in the presence of CaM inhibitors W7 and W13 and the CaM-dependent protein kinase inhibitor KN-62 (Mirzayans et al. 1995). CaM can influence the transduction of growth factor signals via the receptor kinases by modulating their phosphorylation by means of CaM-dependent protein kinases. Thus one can visualise several ways in which CaM could regulate physiological processes.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment