Nucleoside diphosphate kinase-B (NDPKB) (Gilles A.-M. et al., 1991)
Nonmetastatic protein 23B (nm23B)
NME2
NM23-2, nm23-2
Gene: maps to 17q21-q22. It is separated from the
nm23-H1 gene by no more than 18 kb. The 2 genes may have arisen by a tandem duplication.
mRNA: size: 0.8 kb. At cDNA level, nm23-H2 is 88% identical to
nm23-H1 (Stahl J.A. et al., 1991).
Protein: ~17 kD. Amino acid differences between
nm23-H1 and nm23-H2 are highly conservative in hydrophobicity and charge, bringing the total homology of the two proteins to 98% (Stahl J.A. et al., 1991).
Nm23 is a heterodimeric protein which acts as a nucleoside diphosphate (NDP) kinase (Gilles et al., 1991). Nm23-H1 and nm23-H2 encode the A and B polypeptide chains of the enzyme. Each chain consists of 152 amino acid residues. NDP kinases are involved in the synthesis of nucleoside triphosphates, and the nm23 protein may act in the regulation of signal transduction by complexing with G proteins, causing activation/inactivation of developmental pathways.
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. Nm23-H2 has been identified as this human PuF factor (Postel E.H., 1996).
Cell lines:
- The distribution of the
A (nm23-H1) and B (nm23-H2) NDP kinases was analyzed by immunocytofluorescence microscopy in human BCC lines (MCF-7 and MDA-MB-231) using highly specific polyclonal and monoclonal antibodies. Interphasic cells exhibited a granular and filamentous cytoplasmic staining, particularly intense around nuclei, with both anti-
NDP kinase A (nm23-H1) and B (nm23-H2) antibodies. The filamentous component observed with either anti-
A (nm23-H1) or anti-B (nm23-H2) antibodies was altered in parallel to tubulin labeling with compounds interacting with microtubules, such as taxol and colchicine. Confirming published biochemical data, a partial colocalization with the
vimentin network was observed in the MDA-MB-231 cell line. A nuclear and nucleolar localization of NDP kinase B (nm23-H2) was shown by confocal microscopy which was not observed with the
A (nm23-H1) enzyme. In dividing cells, NDP kinase labeling was punctiform and was not colocalized with the mitotic spindle. In conclusion, the
A (nm23-H1) and B (nm23-H2) NDP kinases are similarly distributed in cytosol, associated partly to microtubules supporting a role in nucleotide channeling. Only the B (nm23-H2) enzyme is present in nuclei in accord with its role as a DNA binding protein. Their altered localization in dividing cells suggests colocalization with yet unidentified structures which are not intermediate filament aggregates (Pinon V.P. et al., 1999).
Tumors:
- In a series of 130 breast tumors examined immunohistochemically, 73 (56%) and 69 (53%) positively expressed
nm23-HI and -H2 respectively. Expression of
nm23-HI, but not nm23-H2, was inversely associated with lymph-node metastasis (Tokunaga Y. et al., 1993).
- In a study involving 152 breast cancer samples, there was no significant relationship between either of the nm23 isoforms (
nm23-H1, nm23-H2) and
cathepsin D,
uPA,
PAI-1, steroid hormone receptors (
ER,
PgR) or ploidy status. However, a positive correlation was observed between
uPA receptor and both
nm23-H1 (P=0.0018) and nm23-H2 (P=0.0064) (Russell R.L. et al., 1998).
Backer J.M. et al. (1993) Chromosomal localization and nucleoside diphosphate kinase activity of human metastasis-suppressor genes NM23-1 and NM23-2. Oncogene 8, 497-502.
Chandrasekharappa S.C. et al. (1993) The human NME2 gene lies within 18kb of NME1 in chromosome 17. Genes Chromosomes Cancer 6, 245-248.
Gilles A.M. et al. (1991) Nucleoside diphosphate kinase from human erythrocytes: structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme. J. Biol. Chem. 266, 8784-8789.
Kelsell D.P. et al. (1993) Localization of a second NM23 gene, NME2, to chromosome 17q21-q22. Genomics 17, 522-524.
Pinon V.P. et al. (1999) Cytoskeletal association of the
A and B nucleoside diphosphate kinases of interphasic but not mitotic human carcinoma cell lines: specific nuclear localization of the B subunit. Exp. Cell Res. 246, 355-367.
Postel E.H. (1996) NM23 nucleoside diphosphate kinase as a transcriptional activator of c-myc. Curr. Topics Microbiol. Immunol. 213, 233-252 (
Review).
Russell R.L. et al. (1998) Relationship of nm23 to proteolytic factors, proliferation and motility in breast cancer tissues and cell lines. Br. J. Cancer 78, 710-717.
Stahl J.A. et al. (1991) Identification of a second human nm23 gene, nm23-H2. Cancer Res. 51, 445-449.
Tokunaga Y. et al. (1993) Reduced expression of
nm23-H1, but not of nm23-H2, is concordant with the frequency of lymph-node metastasis of human breast cancer. Int. J. Cancer 55, 66-71.
