Regulation of cellular functions by nucleoside diphosphate kinases in mammals

The role of nucleoside diphosphate (NDP) kinases in cell growth, differenti ation, and tumor metastasis in relation to signal transduction was investig ated. The essential role of NDP kinase in cell growth was validated by coup ling between reduced NDP kinase levels, induced by antisense oligonucleotid es, 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 tiss ues, such as the heart and brain, we further examined this possibility usin g the bone tissue (osteoblasts) and a cultured cell line PC12D. The enhance d NDP kinase accumulation was demonstrated in the matured osteoblasts in vi vo and in vitro by immunohistochemistry. In PC12D cells, neurite outgrowth took place in NDP kinase beta-transfected clones without differentiation in ducers, which was accompanied by prolongation of doubling time. Neurite out growth, 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 adeno carcinoma cells (MTLn3) and nm23-H2-transfected human oral squamous cell ca rcinoma cells (LMF4) manifested reduced metastatic potential and were assoc iated with an altered sensitivity to environmental factors, such as motilit y and growth factors. NDP kinase or, compared to NDP kinase beta, was invol ved in a wide variety of the cellular phenomena examined. Taken together ND P kinase isoforms appear to elicit both their own respective and common eff ects. They may have an ability to lead cells to both proliferative and diff erentiated states by modulating responsiveness to environmental factors, bu t their fate seems to depend on their surrounding milieu.