The positive control of cell proliferation by the interplay of calcium ions and cyclic nucleotides. A review

Abstract

Calcium, cyclic AMP, and cyclic GMP do not seem to be involved in proliferative activation of postmitotic differentiated cells. Instead, they are intracycle regulators, and we propose the following working model of their control of the initiation of DNA synthesis. While a role for cyclic GMP cannot yet be defined, a brief postmitotic burst of its synthesis might serve to prevent certain activated cells (e.g. 3T3 mouse cells) from being diverted into a nonproliferating (but still activated) G0 state (Figs. 1 and 17). In a latter part of the G1 phase, something happens to stimulate briefly the synthesis of cyclic AMP which, in turn, drives calcium ions from the mitochondria into the cytosol to activate newly synthesized thymidylate synthetase (or other primed enzymic assemblies) (Fig. 1). Having "turned on" their target enzymes, the accumulated cyclic AMP is destroyed and the excess calcium ions are reaccumulated by the mitochondria to avoid interfering with succeeding reactions. This model predicts that persistent changes in cyclic AMP metabolism and the respiration-linked, calcium-accumulating (ion-buffering) activity of mitochondria may be responsible for the sustained growth of tumors.

Pro‐oxidants and mitochondrial Ca2+: their relationship to apoptosis and oncogenesis

“…The importance of Ca*' in cell proliferation has already been recognized many years ago [34,35]. For instance, oncogenic growth factors such as epidermal or platelet-derived growth factor cause an increase of the cytosolic Ca*' level by stimulating Ca*+ influx into the cell or by release of Ca*' from the endoplasmic reticulum through turnover of phosphatidyl inositols.…”

Magnesium reverses inhibitory effects of calcium deprivation on coordinate response of 3T3 cells to serum

“…In the presence of 15 mM Mg2+, the Ca2+-deprived cultures reached a rate of uridine uptake about equal to that of the controls and remained close to the control levels to the end of the 3-hr experimental period. DISCUSSION Other investigators have proposed that the availability of Ca2+ controls the proliferation of cells, and that it does so by activating a "master reaction" which leads to initiation of DNA synthesis and cell division (10,11 (Fig. 3).…”

“…From these results and several other considerations, we have proposed that variations in the availability of Mg2+ for transphosphorylation reactions within the cell mediate the coordinate response of cells to external effectors (8). Others have proposed that Ca2+ plays a central role in mediating the growth response of cells to external effectors (10). Support for a mediating role for Ca2+ is chiefly based on the observation that drastically lowering the [Ca2+] of the medium inhibits the onset of DNA synthesis and thereby limits the multiplication of cells (11).…”

“…Culture dishes (100 mm) were used in the cation determination experiments. Briefly, the cultures were washed five times with 10 approximately pH 7. For determination of surface-bound cations, they were exposed for 10 sec to either C02-free or carbonated (pH 4) sucrose solutions.…”

Influence of biogenic amines on the growth of xenografted human colorectal carcinomas

“…High intracellular levels of cyclic guanosine monophosphate (cGMP) or treatment with agents that promote the formation of cGMP are associated with rapid cell division in bacteria (Benlohr et al, 1974), meristematic plant cells and mammalian fibroblasts , haemopoietic stem cells (Byron, 1974), lymphocytes (Hadden et al, 1970), granulocyte-macrophage progenitor cells (Kurland et al, 1977), epidermal cells (Voorhees et al, 1973) and intestinal epithelial cells (Tutton, 1976). Cyclic adenosine monophosphate (cAMP), on the other hand, has been shown to inhibit division in many cell types (for a review see Whitfield et al, 1976) and is an important mediator in the process of contact inhibition of cell division (Pastan et al, 1973 permanently suppressed, tumour growth will be resumed because of relative expansion of the subpopulation of resistant cells. Pharmacological factors that could feasibly be responsible for the observed tachyphylaxis include changes in receptor sensitivity or change in the activity of the phosphodiesterases which are responsible for degrading cyclic nucleotides.…”