Negative control of cell proliferation in eukaryotes

Abstract

The nucleoside diphosphate kinase (NDPK/nm23) iso-forms H1 and H2 were localized in hematopoietic tissues. Flow cytometric analysis and enzymatic assays were used to quantify the intracellular and extracellu-lar concentrations of NDPK. Bone marrow CD34 progenitors contained the highest intracellular levels of both nm23-H1 and nm23-H2. Lower levels were measured in more mature bone marrow cells, whereas peripheral blood leukocytes had the lowest expression of nm23. These data suggest a function of NDPK in early hematopoiesis and a down-regulation of NDPK upon differentiation. In addition, an up-regulation of nm23 expression was observed in lymphocytes after induction of proliferation with phytohemagglutinin. Multiparam-eter flow cytometry demonstrated that this up-regulation occurred during the G 0 /G 1-transition. Flow cyto-metric analysis also revealed a weak surface expression of nm23 on a number of hematopoietic cell lines, which was not detected on normal hematopoietic cells. Our data also demonstrated the presence of NDPK in human plasma, probably due to a limited in vivo lysis of red blood cells. Currently, the family of nucleoside diphosphate kinases (NDPK/nm23) 1 consists of four members encoded by the genes nm23-H1, nm23-H2, DR-nm23, and nm23-H4 (1-4). These enzymes share the ability to transfer the terminal phosphate of nucleoside triphosphates to nucleoside diphos-phates. Beside their function to maintain the cellular GTP level (5), several other functions and properties have been assigned to the NDPK family. These include the identity of nm23-H2 to PuF, a transcription factor of the proto-oncogene c-myc (6), the ability of nm23-H1 to suppress the metastatic potential of several tumors and cell lines (1, 7, 8), the association of NDPK with transcription regulating factors such as the retinoic acid receptor-related orphan receptor and the retinoic Z receptor , and with the heat shock protein hsc70 (9, 10). Recently, it was also reported that NDPK has protein kinase activity (11, 12). The importance of nm23 expression in hematopoiesis has been demonstrated by Okabe-Kado et al. (13), who identified NDPK B as a differentiation inhibiting factor (I-factor) in the conditioned medium of the differentiation-resistant mouse M1 cell line and demonstrated that both nm23-H1 and nm23-H2 can inhibit the in vitro induced differentiation of several hema-topoietic cell lines. This inhibition was independent of the phosphotransferase activity as demonstrated with nm23 mutants lacking the enzymatic activity (13-15). Moreover, reported data indicated a correlation between proliferation and nm23 expression in hematopoietic cells. In lym-phoma and monocytic leukemia, overexpression of nm23-H1 was correlated with a higher tumor aggressiveness and resistance to chemotherapy, respectively (16, 17). Up-regulation of nm23-H1 and-H2 was observed in normal lymphocytes induced to proliferate with phytohemagglutinin (PHA) (18, 19). In vitro, DR-nm23 mRNA is up-regulated in CD34 hemato-poietic progenitor cells during early stages of...

Small molecular mass inhibitor of growth of MDCK cells derived from pig spinal cord

“…Most of the known cell growth inhibitors are either proteins with M r of 10–40 × 10 3 or oligopeptides with M r of several hundreds (Epifanova and Brooks, 1994). In contrast, the cell growth inhibitor in the present study is unlikely to be a peptide as is suggested by its resistance to proteases.…”

“…Cell proliferation in eukaryotes is controlled by the interplay between growth inhibitors and growth stimulators, which switch the cells from growth to rest and vice versa (Epifanova and Brooks, 1994). Although growth inhibitors are biologically as fundamental as the stimulators, their structure and function are far less well characterized than those of growth stimulators.…”

“…They vary in both structure and molecular mass, ranging from oligopeptides (Paukovits and Laerum, 1982; Reichelt et al, 1987; Gembitsky et al, 1998) and a small non‐peptide‐like molecule (Røe et al, 1999) to protein‐like macro‐molecules with molecular mass of more than several thousand (Bohmer et al, 1987; McMurray et al, 1993). The known mechanisms of growth inhibitors differ widely owing to the variety of mechanisms for regulating cell proliferation (Epifanova and Brooks, 1994; Macieira‐Coelho, 1998; Smith‐Thomas et al, 1994).…”

Developmental changes in the inhibition of cultured rat uterine cell proliferation by opioid peptides

“…Ample evidence shows that, the opioid peptides are inhibitors of DNA synthesis and cell proliferation in the CNS (Vértes et al . 1982; Zagon & McLaughlin 1991; Epifanova & Brooks 1994; Zagon et al . 2002) and in several peripheral tissues and cells (Maneckjee et al .…”