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HGNC Approved Gene Symbol: NME1
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38) : 17:51,153,559-51,162,168 (from NCBI)
Steeg et al. (1988) gave the name NM23 to a gene they cloned from a murine melanoma cell line. Expression of the gene correlated inversely with metastatic potential. NM23 RNA levels are highest in cell lines with low metastatic potential. RNA levels did not correlate with cell sensitivity to host immune responses. The authors therefore hypothesized that expression of this gene may be associated with intrinsic aggressiveness of the line. Several observations suggested that NM23 activity may be correlated with inhibition of the tumor metastatic process. Bevilacqua et al. (1989) concluded that NM23 RNA levels are differentially expressed in human breast tumors and that low NM23 RNA levels are associated with histopathologic indications of high metastatic potential. The product of the NM23 gene is a nucleoside diphosphate kinase, which has been designated p19/nm23. Keim et al. (1992) presented evidence that the expression of the gene is related to cell proliferative activity.
Rosengard et al. (1989) found that the human NM23 protein has sequence homology over the entire translated region with a developmentally related 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 the changes in malignant progression.
Postel et al. (1993) reported evidence suggesting that the protein encoded by 1 of the 2 closely related NM23 genes (see NME2; 156491) may be a transcription factor. The gene that may be turned on is the MYC oncogene (190080). Although a dozen DNA binding proteins had been identified for the MYC gene, only one, called PuF (for purine-binding factor, because the DNA sequence it recognizes has a high content of purine bases), was known to regulate MYC transcription in vitro. PuF was identified by Postel and her colleagues (Postel et al., 1989; Postel, 1992) as a partially purified HeLa cell (human cervical carcinoma) factor that binds to a nuclease-hypersensitive element (NHE) at positions -142 to -115 of the human MYC P1 promoter and is necessary for efficient P1 and P2 transcription initiation in vitro. Postel et al. (1993) identified the human gene encoding PuF by screening a cervical carcinoma cell cDNA library with a DNA fragment containing PuF binding sites. DNA sequence analysis of recombinant PuF demonstrated perfect identity with the NM23 gene. Although no clear correlation has yet been established between overexpression of MYC and tumor metastasis, the inverse relation between MYC expression and cell differentiation is well documented. Furthermore, Okabe-Kado et al. (1992) identified a differentiation inhibiting factor in the mouse myeloid leukemia cells as a murine homolog of NM23. Findings leave the conundrum of how NM23 can be both a tumor suppressor and an activator of MYC.
Gilles et al. (1991) showed that nucleoside diphosphate kinases A and B are identical to NM23-H1 and NM23-H2, respectively. The genes NME1 and NME2 encode 2 polypeptide chains that are responsible for heterogeneity of the hexameric enzyme.
Using Northern blot analysis of several mouse tissues, Masse et al. (2002) found that mouse Nme1, which they called nm23-M1, was expressed as 2 transcripts due to the use of 2 alternate polyadenylation signals. Expression was highest in the central nervous system, liver, and kidney. In situ hybridization of 15-day postcoitum mouse embryos showed Nme1 expressed predominantly in the central and peripheral nervous system, sensory organs, and thymus.
Ni et al. (2003) cloned a different transcript (designated NM23H1B) of the NM23H1 gene from 18-week-old human fetal brain. The 987-bp cDNA encoded a protein of 177 amino acid residues. Compared with NM23H1, the cDNA contained an additional NH2-terminal region (25 amino acid residues). Bioinformatics analysis showed that the second exon does not exist in NM23H1. The expression pattern of NM23H1B showed that it is ubiquitously expressed in normal tissues (15 tissues except colon) at different levels. The data also indicated that the expression of the transcript in tumors related to tumor differentiation: there was no expression in poorly differentiated breast carcinoma, pancreatic adenocarcinoma, and undifferentiated ovarian carcinoma.
NME1-NME2 Spliced Read-Through Transcript
By EST database analysis, Valentijn et al. (2006) identified a transcript that starts from the NM23H1 promoter and reads through the neighboring NM23H2 gene. This transcript, which they called NM23LV (NM23 long variant), lacks exon 5 of NM23H1, which contains the stop codon, and exon 1 of NM23H2, which is untranslated sequence. The deduced 267-amino acid NM23LV protein has a calculated molecular mass of 33 kD. It has only 7 beta sheets, which cannot adapt to the antiparallel beta-sheet formation. RT-PCR detected ubiquitous NM23LV expression, with reduced expression in lung and very little expression in kidney. NM23H1, NM23H2, and NM23LV were highly expressed in 8 neuroblastoma cell lines examined, but they were not expressed in HEK293 cells. Western blot analysis detected NM23LV at an apparent molecular mass of 33 kD.
MacDonald et al. (1996) performed site-directed mutagenesis on the NM23-H1 gene and transfected the mutant DNAs into human breast carcinoma cells. They found that mutations of proline-96 or serine-120 reduce the ability of NM23-H1 to inhibit cell motility. In the wildtype protein, serine-120 is a site of phosphorylation; proline-96 is part of a loop of unknown function.
Epstein-Barr virus (EBV) is a herpesvirus that causes infectious mononucleosis in adolescents and lymphoproliferative disease (308240) in immunocompromised individuals and is associated with human cancers, including Burkitt lymphoma (BL; 113970), nasopharyngeal cancer (161550), and Hodgkin disease (236000). EBNA3C is a large, EBV-encoded transcription factor that is expressed with other latent nuclear proteins after infection of B lymphocytes. It upregulates expression of the EBV and complement receptor, CD21 (120650), as well as EBV latent membrane protein (LMP1). Subramanian et al. (2001) showed that the C-terminal region of EBNA3C (amino acids 365 to 992), without which EBV cannot immortalize B lymphocytes, interacts with NME1. Immunofluorescence microscopy demonstrated colocalization of NME1 in nuclei of B cells expressing EBNA3C. Expression of EBNA3C reversed the ability of NME1 to inhibit migration of BL and breast carcinoma (114480) cells.
There is evidence that the NM23 genes, initially documented as suppressors of the invasive phenotype in some cancer types, are involved in the control of normal development and cell differentiation (Lombardi et al., 2000).
Granzyme A (GZMA; 140050) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GZMA-activated DNase (GAAD) is in an endoplasmic reticulum-associated complex containing pp32 (600832) and the GZMA substrates SET (600960), HMG2 (163906), and APE1 (107748). Fan et al. (2003) showed that GAAD is NM23H1 and its specific inhibitor (IGAAD) is SET. NM23H1 bound SET and was released from inhibition by GZMA cleavage of SET. After GZMA loading or cytotoxic T lymphocyte attack, SET and NM23H1 translocated to the nucleus and SET was degraded, allowing NM23H1 to nick chromosomal DNA. GZMA-treated cells with silenced NM23H1 expression were resistant to GZMA-mediated DNA damage and cytolysis, while cells overexpressing NM23H1 were more sensitive.
Using a Drosophila model system, Dammai et al. (2003) showed that the Drosophila NME1 homolog, awd, regulates trachea cell motility by modulating FGFR (see 136350) levels through a dynamin (see 602377)-mediated pathway.
Boissan et al. (2014) found that knockdown of nucleoside diphosphate kinases (NDPKs) NM23H1/H2 (NME1/NME2; 156491), which produce GTP through ATP-driven conversion of GDP, inhibited dynamin-mediated endocytosis. NM23H1/H2 localized at clathrin-coated pits and interacted with the proline-rich domain of dynamin. In vitro, NM23H1/H2 were recruited to dynamin-induced tubules, stimulated GTP-loading on dynamin, and triggered fission in the presence of ATP and GDP. NM23H4 (NME4; 601818), a mitochondria-specific NDPK, colocalized with mitochondrial dynamin-like OPA1 (605290), which is involved in mitochondria inner membrane fusion, and increased GTP-loading on OPA1. Like OPA1 loss of function, silencing of NM23H4 but not NM23H1/H2 resulted in mitochondrial fragmentation, reflecting fusion defects. Boissan et al. (2014) concluded that NDPKs interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency.
Chen et al. (2015) found that the SCF ubiquitin E3 ligase component FBXO24 (609097) enhanced proteasome-mediated degradation of the multifunctional kinase NDPKA in HeLa and HEK293 cells by promoting polyubiquitination of NDPKA on lys85 (K85). FBXO24 interacted with leu55 (L55) and lys56 (K56) of NDPKA, and GCN5 (KAT2A; 602301)-mediated acetylation of K56 abrogated the interaction of FBXO24 with NDPKA, stabilizing NDPKA against proteasome-mediated degradation. Knockdown of FBXO24 via short hairpin RNA, or mutation of the LK motif in NDPKA, increased NDPKA stability. Stabilizing mutations in NDPKA also inhibited cell migration in a wound-healing assay.
Dooley et al. (1994) isolated and sequenced genomic PCR fragments that included the entire coding region of the NME1 gene, revealing that the gene consists of 5 exons and 4 introns spanning 8.5 kb. Comparison with the homologous gene in the rat showed that the exon-intron boundaries are well conserved between the 2 species.
Masse et al. (2002) determined that the mouse Nme1 gene contains 5 exons and spans about 9.0 kb, similar to the human gene. The promoters of the mouse and human NME1 genes, like those of other NME genes, contain several binding sites for AP2 (107580), NF1 (613113), Sp1 (189906), LEF1 (153245), and response elements to glucocorticoid receptors (138040). There are no TATA or CAAT boxes or pyrimidine-rich initiator (Inr) sequences.
NM23 was assigned to 17q12-q21 by in situ hybridization, by analysis of somatic cell hybrids, and by linkage studies with markers in the CEPH panel (Leone et al., 1991). Somatic allelic deletion of the gene was observed in DNA from human breast, renal, colorectal, and lung carcinomas. In several cases the deletion of NM23 was independent of other chromosome 17 deletions. Eddy et al. (1991) mapped the NME1 gene to 17p11-qter by analysis of human-mouse somatic cell hybrid DNAs. Varesco et al. (1992) mapped the gene to 17q22 by in situ hybridization. They also demonstrated a 2-allele polymorphism with BglII. By linkage studies using markers for the NME1 locus, Sudbrak et al. (1993) demonstrated localization of NME1 on 17q. Ni et al. (2003) mapped the NM23H1 gene to chromosome 17q21.3 using bioinformatics analysis.
Whereas reduced expression of NM23 is associated with a high potential for metastasis in some tumor types, its expression is increased in aggressive neuroblastoma (256700). Chang et al. (1994) looked for mutations in the NM23 gene in 24 primary neuroblastoma tumors at different stages of the disease by use of PCR combined with SSCP analysis and Southern blotting. They found an acquired ser120-to-gly (S120G) substitution in 6 of 28 advanced tumors but in none of 22 limited-stage tumors. They indicated that the mutant enzyme still retains its catalytic activity but is more susceptible to the denaturation.
Bevilacqua, G., Sobel, M. E., Liotta, L. A., Steeg, P. S. Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res. 49: 5185-5190, 1989. [PubMed: 2475243]
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Chang, C. L., Zhu, X., Thoraval, D. H., Ungar, D., Rawwas, J., Hora, N., Strahler, J. R., Hanash, S. M., Radany, E. nm23-H1 mutation in neuroblastoma. (Letter) Nature 370: 335-336, 1994. [PubMed: 8047138] [Full Text: https://doi.org/10.1038/370335a0]
Chen, W., Xiong, S., Li, J., Li, X., Liu, Y., Zou, C., Mallampalli, R. K. The ubiquitin E3 ligase SCF-FBXO24 recognizes deacetylated nucleoside diphosphate kinase A to enhance its degradation. Molec. Cell. Biol. 35: 1001-1013, 2015. [PubMed: 25582197] [Full Text: https://doi.org/10.1128/MCB.01185-14]
Dammai, V., Adryan, B., Lavenburg, K. R., Hsu, T. Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/dynamin during tracheal development. Genes Dev. 17: 2812-2824, 2003. [PubMed: 14630942] [Full Text: https://doi.org/10.1101/gad.1096903]
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Fan, Z., Beresford, P. J., Oh, D. Y., Zhang, D., Lieberman, J. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 112: 659-672, 2003. Note: Erratum: Cell 115: 241 only, 2003. [PubMed: 12628186] [Full Text: https://doi.org/10.1016/s0092-8674(03)00150-8]
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MacDonald, N. J., Freije, J. M. P., Stracke, M. L., Manrow, R. E., Steeg, P. S. Site-directed mutagenesis of nm23-H1: mutation of proline 96 or serine 120 abrogates its motility inhibitory activity upon transfection into human breast carcinoma cells. J. Biol. Chem. 271: 25107-25116, 1996. [PubMed: 8810265] [Full Text: https://doi.org/10.1074/jbc.271.41.25107]
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Ni, X., Gu, S., Dai, J., Cheng, H., Guo, L., Li, L., Ji, C., Xie, Y., Ying, K., Mao, Y. Isolation and characterization of a novel human NM23-H1B gene, a different transcript of NM23-H1. J. Hum. Genet. 48: 96-100, 2003. [PubMed: 12601555] [Full Text: https://doi.org/10.1007/s100380300014]
Okabe-Kado, J., Kasukabe, T., Honma, Y., Hayashi, M., Henzel, W. J., Hozumi, M. Identity of a differentiation inhibiting factor for mouse myeloid leukemia cells with NM23/nucleoside diphosphate kinase. Biochem. Biophys. Res. Commun. 182: 987-994, 1992. [PubMed: 1311576] [Full Text: https://doi.org/10.1016/0006-291x(92)91829-f]
Postel, E. H., Berberich, S. J., Flint, S. J., Ferrone, C. A. Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261: 478-480, 1993. [PubMed: 8392752] [Full Text: https://doi.org/10.1126/science.8392752]
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Sudbrak, R., Golla, A., Hogan, K., Powers, P., Gregg, R., Du Chesne, I., Lehmann-Horn, F., Deufel, T. Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha-1, beta-1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. Hum. Molec. Genet. 2: 857-862, 1993. [PubMed: 8395939] [Full Text: https://doi.org/10.1093/hmg/2.7.857]
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Varesco, L., Caligo, M. A., Simi, P., Black, D. M., Nardini, V., Casarino, L., Rocchi, M., Ferrara, G., Solomon, E., Bevilacqua, G. The NM23 gene maps to human chromosome band 17q22 and shows a restriction fragment length polymorphism with BglII. Genes Chromosomes Cancer 4: 84-88, 1992. [PubMed: 1377015] [Full Text: https://doi.org/10.1002/gcc.2870040113]