The regulation of cell proliferation by calcium and cyclic AMP

Abstract

Calcium, in partnership with cyclic AMP, controls the proliferation of non-tumorigenic cells in vitro and in vivo. While it does not seem to be involved in the proliferative activation of cells such as hepatocytes (in vivo) or small lymphocytes (in vitro), it does control two later stages of prereplicative (G1) development. It must be one of the very many regulatory and permissive factors affecting early prereplicative development, because severe calcium deprivation reversibly arrests some types of cell early in the G1 phase of their growth-division cycle in vitro. However, calcium more specifically and much more often regulates a later (mid or late G1) stage of prereplicative development. Thus, regardless of its severity or the type of cell, calcium deprivation in vitro or in vivo reversibly stops proliferative development at that part of the G1 phase in which the cellular cyclic AMP content transiently rises and the synthesis of the four deoxyribonucleotides begins. The evidence points to calcium and the cyclic AMP surge being co-generators of the signal committing the cell to DNA synthesis. The evidence is best explained so far by the cyclic AMP surge causing a surge of calcium ions which combine with molecules of the multi-purpose, calcium-dependent, regulator protein calmodulin (CDR) somewhere between the cell surface and the cytosol. The resulting Ca-calmodulin complexes then stimulate many different (and possibly membrane-associated) enzymes such as protein kinases, one of which produces the DNA-synthetic initiator. Calcium has little or no influence on the proliferation of tumor cells. Some possible explanations of this very important loss of control are considered.

Stimulation of creatine kinase activity in rat skeletal tissue in vivo and in vitro by protease-resistant variants of parathyroid hormone fragments

“…Therefore an indirect mechanism via the increase in cyclic AMP caused by PTH in osteoblasts [26] has been considered to lead to bone resorption [27]. PTH also caused, by a cyclic AMPindependent mechanism [28] involving a Ca2+/phosphoinositide pathway [20,29,30], increased cell proliferation in rat osteoblasts and increased DNA synthesis in chicken osteoblasts and chondroblasts [31][32][33], and in rat calvaria [20]. Moreover, we found Thr for Leu-37, or the substitution of Met for Phe-34 alone, produced 100 %-resistant fragments.…”

Stimulation of cell proliferation in skeletal tissues of the rat by defined parathyroid hormone fragments

“…PTH also causes increased proliferation of thymus, bone marrow and liver in vivo [18], increases which are mediated by changes in Ca2l and/or cyclic AMP concentrations, in a variety of cell culture systems [8,17]. As well as increasing adenylate cyclase activity [19], PTH increases the proliferation [13,14] of cultured bone cells, osteosarcoma cells and chondroprogenitor cells [20].…”

Calcium intake and breast cancer risk: meta-analysis of prospective cohort studies

“…Dietary and lifestyle factors may have an important role in the development of breast cancer (2)(3)(4) , among which Ca intake has been suggested as a potential protective factor in mounting experimental research (5)(6)(7)(8)(9)(10) and several observational studies (11)(12)(13) . A metaanalysis by Chen et al (14) involving six prospective cohorts and nine case-control studies suggested a significant inverse association between Ca intake and risk of breast cancer, with a summary relative risk (RR) of 0·81 (95 % CI 0·72, 0·90) for the highest compared with the lowest intake of Ca, with a significant publication bias.…”