Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development

Abstract

Tumour metastasis is the principal cause of death for cancer patients. We have identified the nm23 gene, for which RNA levels are reduced in tumour cells of high metastatic potential. In this report we identify the cytoplasmic and nuclear Nm23 protein, and show that it also is differentially expressed in metastatic tumour cells. We also find that the human Nm23 protein has sequence homology over the entire translated region with a recently described developmentally regulated protein in Drosophila, encoded by the abnormal wing discs (awd) gene. Mutations in awd cause abnormal tissue morphology and necrosis and widespread aberrant differentiation in Drosophila, analogous to changes in malignant progression. The metastatic state may therefore be determined by the loss of genes such as nm23/awd which normally regulate development.

Identification of an Ecto-nucleoside Diphosphokinase and Its Contribution to Interconversion of P2 Receptor Agonists

“…NDPK also has been proposed to play a major role in the cytosolic synthesis of nucleoside triphosphates in addition to ATP and in maintaining a relative balance in the concentrations of nucleoside triphosphates. Human nm23 genes encode for nucleoside diphosphokinases (14,15), and an inverse relationship exists between nm23 expression and metastatic potential (16,17).In contrast to its well established significance in intermediary metabolism, the potential location and function of NDPK as an extracellular enzyme involved in the transfer of terminal phosphates between extracellular nucleotides has not been determined. Therefore, we have tested this possibility using 1321N1 human astrocytoma cells stably expressing the P2Y 4 receptor which we show is selectively activated by UTP.…”

“…NDPK also has been proposed to play a major role in the cytosolic synthesis of nucleoside triphosphates in addition to ATP and in maintaining a relative balance in the concentrations of nucleoside triphosphates. Human nm23 genes encode for nucleoside diphosphokinases (14,15), and an inverse relationship exists between nm23 expression and metastatic potential (16,17).…”

Nucleoside diphosphate kinases (NDPKs) in animal development

“…Results obtained from Drosophila converged with human studies, and it became clear that AWD is the Drosophila homolog of NM23, given that AWD shows 78 % amino acid identity with the two closely related human proteins NM23-H1/H2 [31]. Next, several parallel studies set out to determine the enzymatic 'activities' of NM23/AWD family proteins.…”

Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein βγ dimers: consequences on G protein activation and stability

“…In mammalian tissues, the cytosolic enzyme forms heterohexamers of 17-21 kDa subunits (Gilles et al 1991;Janin et al 2000). These are composed of different combinations of the three major isoforms, NDPK A, B and C. In addition to NTP synthesis, NDPKs are involved in a variety of processes in cellular physiology, including tumour metastasis (Steeg et al 1988), development (Rosengard et al 1989), gene regulation (Postel 2003), apoptosis (Fan et al 2003), endocytosis (Krishnan et al 2001;Palacios et al 2002), vesicular transport from the endoplasmatic reticulum (Kapetanovich et al 2005) and regulation of the cystic fibrosis transmembrane conductance regulator (Crawford et al 2006a).…”