Retinoic acid responsive gene product, midkine, has neurotrophic functions for mouse spinal cord and dorsal root ganglion neurons in culture

Michikawa, Makoto; Kikuchi, Seiji; Muramatsu, Hisako; Muramatsu, Takashi; Kim, S. U.

doi:10.1002/jnr.490350509

Cited by 129 publications

(78 citation statements)

References 36 publications

(31 reference statements)

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“…First, a pivotal role of MK in the migration of inflammatory cells has been revealed by studies involving MK knockout mice; MK-deficient mice are more resistant to vascular restenosis and nephritis induced by reperfusion (Horiba et al, 2000;Sato et al, 2001). Second, MK exhibits neuroprotective activity (Michikawa et al, 1993;Unoki et al, 1994;Owada et al, 1999), and enhances neurite extension . Induction of MK expression has been detected in reactive astrocytes in ischaemic lesions in human and animal brains (Wang et al, 1998;Wada et al, 2002).…”

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confidence: 99%

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

et al. 2003

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The heparin-binding growth factor midkine (MK) is the product of a retinoic acid-responsive gene, and is implicated in neuronal survival and differentiation, and carcinogenesis. We previously reported that MK mRNA expression is elevated in neuroblastoma specimens at all stages, whereas pleiotrophin, the other member of the MK family, is expressed at high levels in favourable neuroblastomas. As MK is a secretory protein, it can be detected in the blood. Here, we show a significant correlation of the plasma MK level with prognostic factors of neuroblastomas. The plasma MK level was determined in 220 patients with neuroblastomas, and compared with that in children without malignant tumors (n ¼ 17, o500 pg ml À1 ). The plasma MK level became significantly elevated with advancing stages (stage 1: 445 pg ml À1 (median), n ¼ 73; stage 2: 589, n ¼ 39; stage 3: 864, n ¼ 40; stage 4: 1445, n ¼ 56; and stage 4S: 2439, n ¼ 12). More importantly, a higher MK level was strongly correlated with poor prognostic factors: over 1 year of age (P ¼ 0.0299), MYCN amplification (Po0.0001), low TrkA expression (P ¼ 0.0005), nonmass screening, sporadic neuroblastomas (Po0.0001), and diploidy/tetraploidy (P ¼ 0.0007). Thus, these results demonstrate that the plasma MK level is a good marker for evaluating the progression of neuroblastomas. Moreover, considering the ability of antisense MK oligodeoxyribonucleotide to suppress tumour growth of colorectal carcinoma cells in nude mice, as recently reported, the present study suggests that MK is a possible candidate molecular target for therapy for neuroblastomas.

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Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

et al. 2003

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“…Midkine (MK), originally isolated as a product of a retinoic acid-responsive gene in an embryonal carcinoma cell differentiation system, is a heparin-binding growth factor (Kadomatsu et al, 1988;Tomomura et al, 1990 a,b) implicated in neuronal survival and differentiation (Muramatsu and Muramatsu, 1991;Michikawa et al, 1993;Unoki et al, 1994), carcinogenesis (Tsutsui et al, 1993;Nakagawara et al, 1995), fibrinolysis (Kojima et al, 1995), wound healing (Yoshida et al, 1995) and development (Kadomatsu et al, 1990;Mitsiadis et al, 1995a, b). MK belongs to a novel growth factor family whose only members so far are MK and pleiotrophin (PTN)/HB-GAM (Muramatsu, 1993(Muramatsu, , 1994.…”

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Midkine induces the transformation of NIH3T3 cells

Kadomatsu

Hagihara²,

Akhter³

et al. 1997

Br J Cancer

138

111

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Summary Midkine (MK) is a heparin-binding growth factor and is frequently expressed at high levels in many human carcinomas. To investigate further the roles of MK in the regulation of cell growth, we introduced MK expression in NIH3T3 cells. A mixture of transfectants of an MK expression vector, but not a control vector, formed colonies in soft agar, showed an elevated cell number at confluence, and formed tumours in nude mice. An interesting characteristic of the transformed cells was that they became spontaneously detached from the culture dish substratum. In the transformed cells, MK was not only secreted, but also localized, in the perinuclear region as spots. The present data indicate that MK has the potential to transform NIH3T3 cells and suggest that overexpression of the MK gene may promote unregulated cell growth in vivo.

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“…MK and PTN are conserved between mammalian species, and both are distinct from other heparin binding growth factors such as basic and acidic fibroblast growth factors (6,10,12). MK is mitogenic to a number of cell lines and induces neurite outgrowth of embryonic brain cells, PC 12 cells, and dorsal root ganglion cells (12)(13)(14)(15). MK also promotes survival of retinal cells in vivo, astrocytes and mesencephalic neurons in culture (17-16).…”

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Midkine Induces Tumor Cell Proliferation and Binds to a High Affinity Signaling Receptor Associated with JAK Tyrosine Kinases

Ratovitski¹,

Kotzbauer²,

Milbrandt³

et al. 1998

Journal of Biological Chemistry

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The G401 cell line derived from a rhabdoid tumor of the kidney secretes the heparin-binding growth factors midkine and pleiotrophin. Both proteins act as mitogens for diverse cells, but only midkine serves as an autocrine mitogen for G401 tumor cells. We show that midkine specifically binds a protein or complex of molecular mass greater than 200 kDa with high affinity (K d ‫؍‬ 0.07 ؎ 0.01 nM). Midkine, but not pleiotrophin, stimulates tyrosine phosphorylation of several cellular proteins with molecular mass of 100, 130, and 200؉ kDa. Upon midkine binding, the midkine-receptor complex associates with the Janus tyrosine kinases, JAK1 and JAK2. MK stimulates tyrosine phosphorylation of JAK1, JAK2, and STAT1␣. Our initial characterization of the midkine receptor suggests that midkine autocrine stimulation of tumor cell proliferation is mediated by a cell-surface receptor which in turn might activate the JAK/STAT pathway.Mesenchymal-epithelial interactions during development involve reciprocal inductive stimuli that are critically important in the regulation of cellular proliferation, differentiation, and tissue morphogenesis. The elucidation of the molecular basis for these events is a major goal relevant to advancing our understanding of basic developmental processes. Kidney organogenesis depends upon a set of molecular signaling events that form the basis for the induction of nephron formation in the metanephric mesenchyme by the ureteric bud (1, 2). Midkine (MK), 1 a recently identified growth factor, may play an important regulatory role at sites of mesenchymal-epithelial interaction during tooth development and during organogenesis of the kidney (3, 4).MK and pleiotrophin (PTN) are developmentally regulated heparin-binding proteins that regulate cell growth, survival, and differentiation (5-8). Both MK and PTN are products of retinoic acid-responsive genes (8). Expression of PTN is also regulated by platelet-derived growth factor (9). Mature MK and PTN are basic, cysteine-rich polypeptides of 123 and 136 amino acids, respectively, with approximately 50% homology to each other (5, 10, 11). MK and PTN are conserved between mammalian species, and both are distinct from other heparin binding growth factors such as basic and acidic fibroblast growth factors (6,10,12). MK is mitogenic to a number of cell lines and induces neurite outgrowth of embryonic brain cells, PC 12 cells, and dorsal root ganglion cells (12)(13)(14)(15). MK also promotes survival of retinal cells in vivo, astrocytes and mesencephalic neurons in culture (17-16). MK stimulates differentiation of P19 embryonic carcinoma cells into nerve cells, and this stimulation is inhibited by anti-MK antibodies (17). In addition, MK enhances plasminogen activator and plasmin activity in a dose-and time-dependent manner, implying a role for MK in tissue repair and angiogenesis (18 -20).MK is expressed in a characteristic pattern in the developing embryo and may play a role in neurogenesis, kidney organogenesis, and in mesodermal-epithelial interactions (3, 4, 19...

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Retinoic acid responsive gene product, midkine, has neurotrophic functions for mouse spinal cord and dorsal root ganglion neurons in culture

Cited by 129 publications

References 36 publications

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

Midkine induces the transformation of NIH3T3 cells

Midkine Induces Tumor Cell Proliferation and Binds to a High Affinity Signaling Receptor Associated with JAK Tyrosine Kinases

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