Regulation of cellular functions by nucleoside diphosphate kinases in mammals.

The role of nucleoside diphosphate (NDP) kinases in cell growth, differentiation, and tumor metastasis in relation to signal transduction was investigated. The essential role of NDP kinase in cell growth was validated by coupling between reduced NDP kinase levels, induced by antisense oligonucleotides, and the suppression of proliferative activity of a cultured cell line. In addition, because NDP kinase levels are often enhanced with development and differentiation, as has been demonstrated in postmitotic cells and tissues, such as the heart and brain, we further examined this possibility using the bone tissue (osteoblasts) and a cultured cell line PC12D. The enhanced NDP kinase accumulation was demonstrated in the matured osteoblasts in vivo and in vitro by immunohistochemistry. In PC12D cells, neurite outgrowth took place in NDP kinase beta-transfected clones without differentiation inducers, which was accompanied by prolongation of doubling time. Neurite outgrowth, triggered by nerve growth factor and a cyclic AMP analog, was down-regulated upon forced expression of inactive mutant NDP kinase by virtue of a dominant negative effect. NDP kinase alpha-transfected rat mammary adenocarcinoma cells (MTLn3) and nm23-H2-transfected human oral squamous cell carcinoma cells (LMF4) manifested reduced metastatic potential and were associated with an altered sensitivity to environmental factors, such as motility and growth factors. NDP kinase alpha, compared to NDP kinase beta, was involved in a wide variety of the cellular phenomena examined. Taken together, NDP kinase isoforms appear to elicit both their own respective and common effects. They may have an ability to lead cells to both proliferative and differentiated states by modulating responsiveness to environmental factors, but their fate seems to depend on their surrounding milieu.