Disease relevance of NME1

• A proximal region affected by LOH is located in a 22-cM region defined by D17S73 and NME1 and thus is similar in location to the region thought to contain the BRCA1 gene associated with familial breast and breast/ovarian cancer [1].
• This region is linked to the early onset breast/ovarian locus (BRCA1) and allelic deletions of NME1 have been associated with metastatic potential of colorectal carcinomas [2].
• Lymph node metastasis was correlated with LOH at NME1 [3].
• A similar ser120-gly mutation in NME1 has been found in human neuroblastoma, suggesting that mutation in this region may be a general phenomenon related to tumor progression [4].
• Frequent loss of heterozygosity for Rb, TP53, and chromosome arm 3p, but not NME1 in squamous cell carcinomas of the supraglottic larynx [5].

High impact information on NME1

• We show that GAAD is NM23-H1, a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor (IGAAD) is SET [6].
• GzmA-treated cells with silenced NM23-H1 expression are resistant to GzmA-mediated DNA damage and cytolysis, while cells overexpressing NM23-H1 are more sensitive [6].
• Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor [6].
• The human nm23-H1 gene is a suppressor of solid tumour metastasis in some types of cancer [7].
• Granzyme A (GzmA) triggers cell death with apoptotic features by targeting the endoplasmic reticulum-associated SET complex, which contains the GzmA-activated DNase NM23-H1, its inhibitor SET, and Ape1 [8].

Chemical compound and disease context of NME1

• We also studied the effect of resveratrol on a panel of MDA-MB-435 cells transfected with nm23-H1 and nm23-H2 genes, which have been suggested to play a role in controlling metastasis in breast cancer cells [9].
• NM23 gene expression in human prostatic carcinomas and benign prostatic hyperplasias: altered expression in combined androgen blockaded carcinomas [10].
• Expression of nm23-H1 gene product in sarcomatous cancer cells of renal cell carcinoma: correlation with tumor stage and expression of matrix metalloproteinase-2, matrix metalloproteinase-9, sialyl Lewis X, and c-erbB-2 [11].
• The purposes of this study were to determine whether NME1 expression was responsible for metastasis suppression in neo6/melanoma hybrids, and whether genes on chromosome 6 regulate NME1 [12].
• Formalin-fixed, paraffin-embedded archival tissue from 87 carcinomas (Ta-T1 45 cases) and T2-T4 (42 cases) was immunostained (Strept ABC/HRP) with the NDPK-A monoclonal antibody (NDPK-A) against nm23-H1 protein [13].

Biological context of NME1

• The human NME2 gene lies within 18kb of NME1 in chromosome 17 [14].
• To examine the possible tumour suppressor gene role of NME1 in ovarian tumours, 76 patients were investigated by Southern blot analysis to determine the rate of allelic deletion [15].
• The NME1 gene, localized to human chromosome 17 at q22, shows reduced expression in tumors of high metastatic potential [14].
• We have isolated and characterized five yeast artificial chromosome (YAC) clones and three cosmid clones that contain both genes, demonstrating that the NME2 gene is also located on chromosome 17 and is separated by not more than 18 kb from the NME1 gene [14].
• METHODS: We examined 104 invasive ovarian cancers for MSI with six microsatellite markers (BAT25, BAT26, D5S346, D2S123, D17S250 and NME1) [16].

Anatomical context of NME1

• NDP kinase A was transiently located in round spermatid nuclei and became asymmetrically distributed in the cytoplasm at the nuclear basal pole of elongating spermatids [17].
• It also was reported that extracellular NM23 could inhibit differentiation of certain hematopoietic cell lines [18].
• MATERIALS AND METHODS: To study the effect on the earlier stages of hematopoietic maturation, NM23 was added to serum-free pre-colony-forming unit (pre-CFU) assays starting from immature CD34++CD38- bone marrow cells [18].
• In contrast, terminal differentiation of CD34+CD38+ progenitor cells in CFU assays was significantly altered by addition of NM23 protein [18].
• More erythroid burst-forming units and fewer macrophage colonies were observed in cultures containing any of the NM23 isoforms examined [18].

Associations of NME1 with chemical compounds

• OBJECTIVE: We previously demonstrated the presence of nucleoside diphosphate kinase NDPK/NM23 in normal human plasma [18].
• Transfection of the nm23-H1 gene into human hepatocarcinoma cell line inhibits the expression of sialyl Lewis X, alpha1,3 fucosyltransferase VII, and metastatic potential [19].
• No effect was observed on cellular proliferation, nor were the serine 44 to alanine nm23-H1 mutant transfectants motile, demonstrating the specificity of the data [20].
• The proline 96 k-pn, serine 120 to glycine, and to a lesser extent serine 120 to alanine mutant nm23-H1-transfected cell lines exhibited motility levels at or above the control transfectants, indicating that these mutations can abrogate the motility-suppressive phenotype of nm23-H1 [20].
• In neutrophils, only one acidic isoform of each NDPKA and NDPKB was labelled in the presence of EDTA [21].

Physical interactions of NME1

• The centrosomal kinase Aurora-A/STK15 interacts with a putative tumor suppressor NM23-H1 [22].
• Moreover, both NM23-H1 and Nm23-H2 bind to nuclease hypersensitive elements in the platelet-derived growth factor PDGF-A gene promoter sequence-specifically, correlating with either positive or negative transcriptional regulation [23].
• Furthermore, the nm23-H1 (-)/E-cadherin (+) coexpression profile was coupled to decreased E-cadherin immunohistochemical protein detection (grade II) in 21% of the cases examined [24].
• The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death [25].

Regulatory relationships of NME1

• In this resistance profile, FOS was up-regulated and NM23 down-regulated [26].
• A novel physical and functional association between nucleoside diphosphate kinase A and AMP-activated protein kinase alpha1 in liver and lung [27].
• Overexpression of nm23H1 inhibited the Tiam1-induced production of GTP-bound Rac1 and activation of c-Jun kinase [28].
• Transient transfection analyses in HepG2 cells revealed that both NM23-H1 and -H2 repressed transcriptional activity driven by the PDGF-A basal promoter (-82 to +8) [29].
• The erythroid differentiation of HEL cells was inhibited by recombinant human nm23-H1, -H2, mouse nm23-M1, and -M2 proteins [30].
• Wild-type NM23-H1 inhibited TGF-beta-induced apoptosis and growth inhibition, whereas NM23-H1(C145S) had no effect [31].

Other interactions of NME1

• Subsequently, two related human nm23 genes, nm23-H1 and nm23-H2, were identified [32].
• Of the 4 loci tested, LOH at TP53, D17S74, and NME1 was associated with clinical stage [3].
• P-glycoprotein, metallothionein and NM23 protein expressions in breast carcinoma [33].
• The higher level of NM23-H1 was correlated with a worse outcome in patients with a single MYCN copy, or in those younger than 12 months of age [34].
• STK15 and NM23 were initially found to interact in yeast in a two-hybrid assay [22].

Analytical, diagnostic and therapeutic context of NME1

• Furthermore, we confirmed that reduced expression of nm23-H1 mRNA was in accordance with a reduced amount of NM23-H1 protein using Western blot analysis [32].
• METHODS: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis [35].
• To investigate if the nm23 genes play a central role in the progression of renal tumors, we have examined nm23-H1 and nm23-H2 gene expression using Northern-blot analysis and immunohistochemistry [36].
• We examined serum NM23-H1 protein levels in 217 patients with neuroblastoma, including 131 found by mass-screening and 86 found clinically by an enzyme-linked immunosorbent assay, and determined the association between levels of this protein, and known prognostic factors or the clinical outcome [34].
• Association of these proteins in human cells was confirmed by co-immunoprecipitation from cell lysates and biochemical fractionation indicating that STK15 and NM23-H1 are present in a stable, physical complex [22].

References