A new function of Nm23/NDP kinase as a differentiation inhibitory factor, which does not require it's kinase activity

Abstract

We recently identified a differentiation inhibiting factor (I-factor) in mouse myeloid leukemia M1 cells as a murine homolog of nm23-H21nucleoside diphosphate kinase (NDPK)-B gene product. We examined the I-factor activities of several authentic nm231NDPK proteins, i.e recombinant rat NDPK a and t, recombinant mouse nm23-M1 and -M2, and recombinant human nm23-H1 and -H2 containing a mutant nm23-H2 his protein lacing NDPK activity. Almost all these nm23/NDPK proteins showed I-factor activity. Moreover, to understand the active domain exhibiting I-factor activity of nm23-H2 protein lacking NDPK activity, we have investigated the I-factor activities of some truncated nm23-H2 proteins. The truncated nm23-H2 protein containing N-terminal peptide 1-60 retained the I-factor activity. These results provide the first evidence for a function of nm23/NDPK as a differentiation inhibiting factor in leukemic cells, that is independent of its NDPK activity and dependent on the presence of N-terminal peptide.

12-O-Tetradecanoylphorbol-13-acetate and UV Radiation-induced Nucleoside Diphosphate Protein Kinase B Mediates Neoplastic Transformation of Epidermal Cells

“…Earlier reports identified NDPK-B as a differentiation-inhibitory factor, which is able to inhibit the differentiation of several hematopoietic cell lines in vitro, where the inhibition was independent of the phosphotranferase activity, as demonstrated with NDPK-B mutants lacking the enzymatic activity (14,49). Moreover, several hematopoietic tumor cell lines stained positive for NDPK-B in flow cytometric analysis (50), and upregulation of the human NDPK-B gene was also observed in normal lymphocytes induced to proliferate with phytohemagglutinin (51).…”

“…NDPKs were originally identified as essential housekeeping enzymes required for the synthesis of nucleoside triphosphates by catalyzing the transfer of the ␥-phosphoryl groups from nucleoside triphosphates to nucleoside diphosphates via a phosphohistidine 118 enzyme intermediate, and they play a role in maintaining intracellular nucleotide concentrations (10). Altered expression of NDPK is also reportedly involved in many cellular processes, including oncogenesis (11,12), cellular proliferation (13), differentiation (14,15), motility (16), development (17), DNA repair (18), and apoptosis (19). In Escherichia coli, NDPK functions as a mutator gene and is not essential for viability (20).…”

Serum levels of the nm23-H1 protein and their clinical implication in extranodal NK/T-cell lymphoma

“…We previously found that a differentiation inhibitory factor (I-factor) purified from a differentiation-resistant mouse myelogenous leukemia cell line was identical to nm23 protein. 1 Recently, we established an enzyme-linked immunosorbent assay (ELISA) technique of determining the serum level of nm23-H1 protein, 2 and reported that the level in patients with aggressive lymphoma was significantly higher than that in healthy individuals. Furthermore, this assay system can be useful to determine the therapeutic strategy for aggressive lymphoma since the prognosis is worse in patients with a high nm23-H1 level.…”

Serum nm23-H1 protein as a prognostic factor in aggressive non-Hodgkin lymphoma

“…19,24 The measurements were made at the Department of Immunology, SRL, Tokyo, Japan. Soluble IL-2R was measured by sandwich ELISA as described in the literature.…”