title: Learning about the functions of NME/NM23: lessons from knockout mice to silencing strategies.
abstract: The human NME gene family (also known as NM23) comprises ten genes that are involved in diverse physiological and pathological processes including proliferation, differentiation, development, ciliary functions, and metastasis. For the moment, only the NME1, NME2, and NME7 genes have been inactivated in transgenic knockout mice, as well as a double NME1-NME2 gene knockout. Mice lacking NME1 or NME2 grow to adulthood without health problems, although NME1 (-/-) mice have modest growth retardation. Double knockout NME1 (-/-)-NME2 (-/-) mice, by contrast, are highly hypotrophic and die at birth from profound anemia due to impaired erythroblast development. Evidence for a metastasis suppressor function of NME1 in vivo comes from crossing NME1 (-/-) mice with mice prone to develop hepatocellular carcinoma; the double transgenic mice present a higher incidence of lung metastases. Silencing of NME1 by siRNA interference has confirmed this function by conferring a "metastatic phenotype" on non-invasive human epithelial cancer cell lines. This function is specific to NME1 and is not observed when the NME2 is silenced. The data indicate that NME1 loss is causally involved at the early stages of the metastatic cascade. NME2 (-/-) mice and NME2 silencing experiments reveal a specific role of NME2 in activation of heterotrimeric G proteins and of KCa3.1 channel in T cells, pointing to a role of NME2 as a histidine phosphotransferase. Regarding NME7, consistent with its expression in axonemal structures, NME7 (-/-) mice present lesions similar to primary ciliary dyskinesia. This review summarizes the recent data obtained by knockout and silencing of NME/NM23 genes that provide mechanistic insights into their respective roles in physiology and pathology.
authors.affiliation: UPMC Université Paris 06, 75005, Paris, France. mathieu.boissan@inserm.fr
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boissan
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Lacombe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000502:physiology*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D021122:Protein Subunits
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; D021122:Protein Subunits