Midkine [Findings and achievements in midkine research]

Midkine home > Achievements

Findings and achievements in midkine research

*Numbers in brackets correspond to the number of original articles in the reference.

*To Go to the Year directly. Choose from pull-down list.

-1993

Discovery of midkine. cDNA cloning of midkine as a product of a gene, the expression of which is increased at the early differentiation stage in embryonal carcinoma cells. (Kadomatsu K. et al., 1988) [1]
Identification of a heparin binding protein in chick embryos, RIHB, which turned out to be chicken midkine. (Vigny, M et al., 1989, Raulias et al., 1991) [2, 11]
The site of strong midkine expression during embryogenesis was identified. (Kadomatsu, K. et al., 1990) [3]
Determination of full cDNA structure of midkine. Midkine was predicted to be a secretary protein. (Tomomura, M. et al., 1990) [4]
Pleiotrophin/ HB-GAM has strong homology with midkine. (Meremies et al., Li, Y. S. et al., 1990) [5, 6]
Structural determination of mouse midkine gene. (Matsubara et al., 1990) [7]
Midkine was verified to be a secreted, heparin binding protein. (Tomomura et al., 1990) [8]
Midkine was purified and was shown to have grow-promoting and neurite-promoting activities. (Muramatsu, H. et al., 1991) [9]
cDNA cloning of human midkine. (Tsutsui, J. et al., 1991) [10]
Determination of chromosomal localization of mouse midkine gene (Mdk). (Shimon-Chazottes, D. et al., 1992) [12]
Importance of midkine in neurogenesis was suggested. (Nurcombe, V. et al., 1992) [13]
Discovery of increased midkine expression in human carcinomas. (Tsutsui, J. et al., 1993) [14]
Midkine promotes survival of neurons. (Michikawa et al., 1993; Satoh, J. et al., 1993) [15, 16]
Midkine accumulates in senile plaques of Alzheimer's disease. (Yasuhara, O. et al., 1993) [17]
Production of antibody to midkine and its application. Midkine promotes growth of Wilms tumor cells. (Muramatsu, H. et al., 1993) [18]
Determination of the secondary structure of midkine. (Fabri, L. et al., 1993) [19]

▲up

1994

Determination of gene structure og human midkine. (Uehara, K. et al., 1993) [20]
Chromososomal localization of human midkine gene (MDK) was determined. (Kanama, T. et al., 1993) [21]
Elevated expression of midkine in breast and lung carcinomas. (Garver, R. I. Jr. et al., 1993, 1994) [22, 23]
Midkine active site is mainly located at the more C-terminaly located domain. (Muramatsu, H. et al., 1994) [24]
Identification of retinoic acid responsive element in the midkine promoter. (Matsubara, S. et al., 1994) [25]
Midkine prevents death of retinal neurons after exposure to constant light. (Unoki, K. et al., 1994) [26]
Midkine binds strongly to nucleolin. (Take, M. et al., 1994) [27]
Midkine is present in the radial glial processes along which neurons migrate. Midkine expression is also correlated with cellebelar development. (Matsumoto, K. et al., 1994) [28, 29]

▲up

1995

Midkine promotes fibrinolytic activity of vascular endothelial cells. (Kojima, S. et al., 1995) [30]
Midkine is involed in tooth morphogenesis (Mitsiadis, T. et al., 1995) [31]
Embryonic distribution of midkine is considerably different from that of pleiotrophin (HB-GAM). (Mitsiadis, T. et al., 1995) [32]
Midkine binds strongly to syndecans. (Mitsiadis, T. et al., 1995; Kojima, T. et al., 1996; Nakanishi, T. et al., 1997)[32, 37, 49]
Patients with neuroblastoma, urinary bladder carcinoma and glioblastoma with strong midkine expression exhibit worse prognosis compared to patients with tumors of low midkine expression. (Nakagawa, A. et al., 1995; OﾕBrien et al., 1996; Mishima et al., 1997) [33, 42, 53]
Elevated expression of midkine in gastrointestinal carcinomas, thyroid carcinoma and brain tumors. (Aridome, K. et al. 1995; Kato et al. 1999, 2000) [34, 63, 72]
Increased midkine expression upon ischemia. (Yoshida, Y. et al., 1995; Obama, Y. et al., 1998) [35, 54]
Midkine is present in the amniotic fluid in large amounts. (Obama, H. et al., 1995) [36]

▲up

1996

Sulfate groups in heparin required for strong binding to midkine was indentified. (Kaneda, N. et al. 1996) [38]
Total chemical synthesis of midkine. (Inui, T. et al., 1995) [39]
WT1 bunding site is pres ent in the midkine promoter. (Adachi, Y. et al., 1996) [40]
Development of enzyme immunoassay of midkine. Serum midkine levels increases in patients with hepatocellular carcinomas. (Muramatsu, H. et al., 1996) [41]
Discovery of truncated midkine. (Kaname, T. et al., 1996) [43]

▲up

1997

Midkine transforms N1H3T3 cells. (Kadomatsu, K., et al., 1997) [44]
Midkine dimerizes upon action to vascular endothelial cells. [45]
Midkine induces synaps formation in neuro-muscular junction. (Zou, H. et al., 1997) [46]
Midkine promotes neutrophil migration (Takada, T. et al., 1997) [47]
Three dimentional structure of midkine has been determined (Iwasaki, W. et al., 1997) [48]
Elucidation of the heparin binding site in midkine (Iwasaki, W. et al.; Asai, T. et al., 1997) [48, 50]
Midkine has in vivo angiogenic activity (Choudhuri, R, et al., 1997) [51]
Midkine is a marker of radial glial process (Sun, X. Z. et al., 1997) [52]

▲up

1998

Midkine gene knockout mice were produced. (Nakamura, E. et al., 1998) [55]
Midkine promotes neurogenesis in Xenopus embryos. (Yokota, C. et al., 1998) [56]
Midkine suppresses cytotoxic activity of amiyloid b-peptide. (Yu, G.S. et al., 1998) [57]

▲up

1999

Midkine promotes the migration of neuronal cells, and receptor-type protein tysosine phosphatase z (PTP z) serves as the receptor in this system. (Maeda, N. et al., 1999) [58]
Midkine expression increases during progression of prostate carcinoma and colon carcinoma. (Konishi, N. et al., Ye, C. et al., 1999) [59, 60]
Anti-apoptotic signal of midkine to neurons is mediated by PI3 kinase and then by ERK. (Owada, K., et al., 1999) [61]
Midkine is involved in repaire of bone fracture, and promotes chondrogenesis. (Ohta, S, et al., 1999) [62]

▲up

2000

Serum midkine levels increase in many cancer patients. (Ikematsu, S, et al., 2000) [64]
Midkine binds strongly to a chondroitin sulfate proteoglycan, PG-M/versican. (Zou, K. et al., 2000) [65]
Chondroitin sulfate E structure is a high affinity binding site of midkine. (Ueoka, C. et al., 2000; Zou, P. et al., 2003) [66, 96]
In midkine gene deficients mice, neomtima formation after ischemia is suppressed. Midkine promotes macrophage migration. (Horiba, M. et al., 2000) [67]
Midkine also binds to sulfatide and glypicans (Kurosawa, N, et al., 2000, 2001) [68, 79]
LRP (low density lipoprotein receptor-related protein) is a component of the midkiine receptor (Muramatsu, H. et al., 2000) [69]
Midkine promotes survival of bovine embryos cultured in vivro. (Ikeda, S. et al., 2000) [70]
Midkine promoter can be utilized to tumor-preferential expression of thymidine kinase. (Adachi, Y. et al., 2000, 2001; Miyauchi, M. et al., 2001; Tomizawa, M. et al., 2003) [71, 75, 76, 94]
Midkine promotes collagen-gel contracting activity of fibroblasts. (Sumi, Y. et al., 2000) [73]
Midkine increases resistance of tumor cells to an anti-tumor drug. (Qi, MS, et al. 2000) [74]

▲up

2001

Mikine inhibits HIV infection. (Callebaut, C. et al., 2001) [77]
The zebrafish has two midkines, and both are involved in neurogenesis. (Winkler, C. et al., 2001, 2003) [78, 93]
Midkine is involved in nephritis after ischemic injury. (Sato, W. et al., 2001) [80]
Midkine is strongly expressed in malignant peripheral nerve sheath tumor, which is caused by the loss of neurofibromatosis-1 gene, and promotes the growth of the tumor. (Mashour, G. A. et al, 2001) [81]
Antisense oligoDNA to midkine inhibits growth of tumor cells implanted into nude mice. (Takei, Y. et al., 2001)[82]
laminin binding protein-precursor binds to midkine strongly and helps its nuclear translocatin. (Salama, R. et al., 2001) [83]
Midkine promotes osteoblast migration. The receptor is PTPz and the downstream signaling system is from PI3 kinese to ERK. (Qi, M.S. et al., 2001) [84]
Midkine delays the process of neuronal death after ischemia. (Yoshida, Y. et al., 2001) [85]

▲up

2002

Nuclear translocation of midkine is required for its cell survival-promoting activity. LRP and nucleolin is involved in internalization and nuclear translocation, respectively (Shibata, Y. et al., 2002) [86]
An action mechanism of midkine in epithelial mesenchymal interaction has been clarified. (Sumi, Y. et al., 2002) [87]
Anaplastic leukemia kinase (ALK) is a receptor of midkine. (Stoica, G. E. et al., 2002) [88]

▲up

2003

Midkine is a useful marker for diagnosis of neuuroblastoma and esophageal carcinoma. (Ikematsu, S. et al., 2003, Shimada, H. et al., 2003) [89, 90, 91]
Urinary midkine can be also a tumor marker (Ikematsu, S. et al., 2003) [92]
A midkine receptor for neuron survival activity is also PTP z. Together with LRP, LRP 6 can be also a component of the receptor complex. (Sakaguchi, N. et al., 2003) [95]
Anti-angiogenesis therapy is effective for treatment of xenograft of bladder carcinoma. (Murakami, M. et al., 2003) [97]
In hepatocarcinoma, midkine promoter is as effective as alpha-fetoprotein promoter in selective expression of downstream toxic genes. (Tomizawa, M. et al., 2003) [98]

▲up

2004

In cell lines from gastric carcimoma, midkine gene is the gene the overexpression of which is most correlated with resistance to anti-tumor drugs. (Kang, H. et al., 2004) [99]
Nuclear targeting of midkine is down regulated by degradation by proteasome. (Suzuki, N. et al., 2004) [100]
Experiments using midkine-deficient mice revealed that midkine plays important roles in intraperitoneal adhesions after surgery. (Inoh, K. et al., 2004) [101]
Expression of truncated midkine is enhanced by base T in G/T polymorphism of base 62 in the midkine gene. (Nobata, S. et al., 2004) [102]
Midkine is strongly expressed upon spinal injury. (Sakakima, H. et al., 2004) [103]
Midkine promoter is better that erbB-2 promoter to express toxic genes in breast carcinoma. (Yu, L. et. al., 2004) [104]
Midkine is strongly involved in etiology of rheumatoid arthritis by promoting both migration of inflammatory leukocytes and differentiation of osteoclasts. (Maruyama, K. et al., 2004) [105]
Apoptosis of hepatocarcinoma cells induced by TRIAL is inhibited by midkine. (Ohuchida, T. et. al., 2004) [106]
Midkine expression in the lung is induced by hypoxia, and HIF alpha is involved in the process. The expressed midkine acts on vascular smooth muscle cells to enhance the expression of certain genes. (Reynolds, P. R. et al., 2004) [107]
A conditionally replicative adenovirus under the control of midkine promoter inhibits the growth of transplanted glioma cells. (Kohno, S. et al., 2004)[108]
Serum midkine level increases in adult patients with neurofibromatosis type I. (Mashou, G. et al., 2004) [109]
Integrins (alpha4beta1 and alpha6beta1) are components of the midkine receptor, and probably co-operate with other receptor proteins. (Muramatsu , H. et al., 2004) [110]
Endogeneous midkine enhances renal toxicity of anti-cancer drug by promoting the migration of inflammatory cells. (Kawai, H. et al., 2004) [111]
Midkine promotes liver regeneration. (Ochiai et al., 2004) [112]
During repair of damaged sciatic nerve, midkine is expressed in spinal motor neurons. (Sakakima, H. et al., 2004) [113]
Antisense oligoDNA was developed to suppress expression of human midkine. (Takei, Y. et al., 2004) [114]

▲up

2005

Antisense oligoDNA to midkine could suppress ischemic renal injury and neointima formation in mice. (Sato, W. et al., Hayashi, K. et al., 2005) [115, 119]
Neuronal death upon ischemic brain injury is partly prevented by introduction of the midkine gene. (Takada, Y. et al., 2005) [116]
Truncated midkine has transforming capability. (Nobata, S. et al., 2005) [117]
Midkine may be involved in the development of endometriosis. (Hirota, Y. et al., 2005) [118]
Truncated midkine is expressed during mouse embryogenesis. (Chen, Q. et al., 2005) [120]
Midkine-a is required for formation of floor plate in the zebra fish. (Schafer, M. et al., 2005) [121]
Serum midkine concentration is increased in about 50 % cases of patients with Alzheimer's disease. (Salama, R. H. et al., 2005) [122]
Resistance to drug resistance is transmitted to other cancer cells by a secretory factor, midkine. (Mirkin, B. L. et al., 2005) [123]
Midkine is a new regulatory factor of the renin-angiotensin pathway. (Ezquerra, L. et al., 2005) [124]
Midkine is involved in development of malignant peripheral nerve sheath tumor. (Friedrich, C. et al., 2005) [125]

▲up

2006

Drosophila melanogaster has two proteins, miple1 and 2, which share a motif with midkine and pleiotrophin. (Englund, C. et al., 2006) [126]
Midkine produced by the host enhances tumor metastasis. (Salama, R. H. et al., 2006) [127]
Midkine is involved in etiology of diabetic nephropathy. (Kosugi, T. et al., 2006) [128]
Mice doubly deficient in midkine and pleiotrophin genes exhibit severe auditory deficit and scarcely express beta-tectorin gene. (Zou, P. et al., 2006) [129]
Midkine expression increases in the brain of patients with chronic alcoholism. (Flatscher-Bader, T. et al., 2006) [130]
In midkine-deficient mice, expression of enzymes involved in catecholamine biosynthesis is dramatically up-regulated.(Ezquerra, L., 2006) [131]
siRNA for midkine enhances the effect of an anti-tumor drug. (Takei, Y. et al., 2006) [132]
Midkine expression increases during healing of the damaged colon. (Yuki, T. et al., 2006) [133]
siRNA for midkine suppresses neointima formation in vein grafts. (Banno, H. et al., 2006) [134]
Neuroglycan C serves as a recetor for midkine upon midkine-dependent process extension of oligodendrocyte precursor-like cells. (Ichihara-Tanaka, K., 2006) [135]
Midkine is strongly expressed in the fetal adrenal, and promotes the growth of definitive zone cells. (Ishimoto, H., 2006) [136]
Midkine signaling through anaplastic lymphoma kinase requires recruitment of insulin receptor substrate-1 and activation of NF-kappaB. (Kuo et al., 2006) [137]
Midkine is strongly expressed in injured colonic mucosa, and promotes healing in the wound repair model. (Yuki et al., 2006) [138]
Midkine is strongly expressed in the regenerating muscle. (Sakakima et al., 2006) [139]
The midkine activity to increase the efficiency of in vitro development of bovine fertilized eggs is partly ascribed to apoptosis inhibitory activity toward cumulus cells. (Ikeda et al., 2006) [140]
Midkine promotes survival of heart cells after ischemic injury. It may be possible to treat heart infarction using midkine. (Horiba et al., 2006) [141]
Substances with midkine inhibitory activity, such as siRNA and chondroitin sulfate E, were helpful for treatment of mouse models of rheumatoid arthritis and adhesion after surgery. (Yamamoto et al., 2006) [142]
Mice deficient in both midkine and pleiotrophin were difficult to be born and small, and exhibited female infertility. (Muramatsu et al., 2006) [143]
Midkine promotes growth and survival of neural precursor cells, and the activity is considered to be the basis of　its activity to enhance neurogenesis. (Zou et al., 2006) [144]

▲up

2007

Morphine and yohimbine enhance midkine expression in the hippocampus. (Ezquerra et al., 2007) [145]
Patients with gastrointestinal stromal tumor with midkine expression exhibit worse prognosis than patients with the tumor without midkine expression. (Kaifi et al., 2007) [146]
Midkine is strongly expressed in human meningiomas and inhibits their apoptosis. (Tong et al., 2007) [147]
Midkine promotes STAT3 phosphorylation in 3T3-L1 cells and their differentiation to adipocytes. (Cernkovich et al., 2007) [148]
Midkine expression is increased in acute B-precursor lymphoblastic leukemia. (Hidaka et al., 2007) [149]
The developing striatum expresses both midkine and pleiotrophin. Pleiotrophin promotes survival of their neurons. (Marchionini et al., 2007) [150]
Midkine is useful as a marker of hepatocellular carcinoma. (Jia et al., 2007) [151]
Intravenous injection of antisense oligoDNA to midkine inhibits growth of human hepatocellular carcinoma grown in mice. (Dai et al., 2007) [152]
Midkine is overexpressed in insulinoma and pancreatic carcinoma. Furthermore, 3 species of cancer-specific truncated midkine were found. (Tao et al., 2007) [153]
The mode of midkine expression is different between sporadic and ulcerative colitis-associated colon carcinomas. (Tokuyama et al., 2007) [154]
Midkine is strongly expressed in osteosarcoma, and anti-midkine antibody inhibits their growth. (Maehara et al., 2007) [155]
Midkine is a marker of lymph node metastasis in oesophageal squamous cell carcinoma. (Krzystek-Korpacka et al., 2007) [156]
Midkine expression is a worse prognostic marker in pancreatic head carcinoma. (Maeda et al., 2007) [157]
Midkine is involved in inflammation of renal tubules upon diabetic nephropathy. (Kosugi et al., 2007) [158]
Growth of ｃolon carcinoma transplanted in nude mice is inhibited by TK under the control of minimal promoter of midkine and ganciclovir. (Hanari et al., 2007) [159]
Miple, which has a common motif of midkine and pleiotrophin in Drosophila, was identified as a target molecule downregulated by HOW, which is involved in correct mesoderm spreading. (Toledano-Katchalski et al., 2007) [160]
Human ovarian follicles strongly express midkine. (Hirota et al., 2007) [161]
The growth of nude mice-transplanted urinary bladder carcinoma is inhibited by adenovirus, E1a of which is under the control of midkine promoter. (Terao et al., 2007) [162]
Midkine is probably involved in cachexia in gastroesophageal cancer patients. (Krzystek-Korpacka et al., 2007) [163]
Midkine activity can be inhibited by midkine-binding domain of LRP. (Chen et al., 2007) [164]

▲up

2008

Zebra fish Midkine-b is involved in development of neural crest cells. (Liedtke and Winkler, 2008 [165]
Midkine probably plays an important role in the etiology of multiple sclerosis as indicated in the mouse model, and an aptamer suppressing midkine action is expected to be helpful in treatment of multiple sclerosis. (Wang et al., 2008)[166]
Midkine expression is increased in the brain of patients with alcohol abuse. (Flatscher-Bader and Wilce, 2008) [167]
Midkine expression is increased is soft-tissue sarcoma. (Jin et al., 2008)[168]

▲up

2009

Acyl-CoA synthase 5 enhances survival of cancer cells　under acidic conditions via enhancement of midkine expression.[169]
Midkine is involved in development of the dopaminergic neural functions. (Ohgate et al., 2009)[170]
Midkine is involved in bothe degeneration and regeneration of injured peripheral neurons. (Sakakima et al., 2009)[171]
Midkine induces hypertension by enhancing the activity of angiotensin-converting enzyme, and is correlated with the onset of hypertension accompanying nephritis. (Hobo et al., 2009)[172]
Solid-phase assay using micro-beads　is useful to detect midkine as a marker of breast carcinoma. (Ibusuki et al., 2009)[173]
Midkine enhances insulin secretion after binding with apolipoprotein A-V. (Helleboid-Chapman et al., 2009)[174]

▲up

2010

In the retina of zebrafish, midkine expression is regulated by circadian clock, not by exposure to light. (Calinescu, A.A. et al., 2009) [175]
Gene transfer of midkine ameliorates cardiac dysfunction after myocardial infarction. (Sumida, A. et al., 2009)[176]
Midkine inhibits trabecular bone formation. (Neunaber, C. et al., 2010)[177]
Midkine and pleiotrophin have antibacterial activity. (Svensson et al., 2010)[178]
Midkine blocks kainic acid-induced seizure. (Kim, Y.B. et al., 2010)[179]
A simple assay for midkine activity was applied to screen midkine inhibitors.(Matsui T. et al., 2010)[180]
Early exercise after brain damage promotes the recovery with concomitant expression of midkine. (Matsuda F. et al., 2010)[181]

▲up

2011

Premature binding of midkine and low density lipoprotein receptor-related protein during biosynthesis hinders the synthesis of the both proteins. (Sakamoto, K. et al., 2011) [182]
Midkine inhibits deposition of amyloid β-peptide plaques. (Muramatsu, H. et al., 2011) [183]
Midkine suppresses proliferation of osteoblasts by inhibiting Wnt-signaling. (Liedert, A. et al., 2011) [184]
Midkine suppresses cell damage upon ischemia-reperfusion in the pig heart. (Ishiguro et al., 2011) [185]
Midkine contributes to development of neuroblastoma through ALK signaling. (Reiff et al., 2011) [186]
Bacteria living in the skin hinder antibacterial activity of midkine by secreting a protease and a midkine-binding protein. (Frick et al., 2011) [187]
Midkine binds to Notch-2, and enhances chemoresistance of pancreatic carcinoma cells through the Notch signaling system.(Gungor et al., 2011) [188]

▲up

2012

Estradiol enhances epithelial-mesenchymal transition of lung carcinoma cells by upregulating midkine expression. (Zao et al., 2012) [189]
Midkine inhibits differentiation of regulatory T cells by suppressing the development of tolerogenic regulatory T cells (Sonobe et al., 2012) [190]
Midkine enhances proliferation of primordial germ cells. (Shen et al., 2012) [191]
Midkine promotes survival of B cells through the PTPζ signaling system. (Cohen et al., 2012) [192]
Midkine, which was induced in endothelial cells upon ischemia-reperfusion, induces angiogenesis. (Weckbach et al., 2012) [193]

▲up

2013

Midkine is protective to glomerular injuries, probably by enhancing fibrinolytic activity through inhibition of PAI-1 (Kojima et al.,2013) [194]
The steric structure of whole midkine molecule has been elucidated. The hinge region is also important for heparin binding (Lim et al., 2013) [195]
Inhibition of neurite outgrowth by chondroitin sulfate can be blocked by midkine. (Muramoto et al., 2013) [196]

▲up

2014

Midkine promotes adhesion of neutrophils via β-2 integrin. The midkine receptor in this occasion is considered to be LRP-1. (Weckbach et al., 2014) [197]
The growth and differentiation of lung epithelial cells under hypoxia conditions depend on expression of midkine mediated by PKCδ (Zhang et al., 2014) [198]
Midkine is produced in adipocyte, inhibits the insulin signsling system and is considered to be involved in insulin resistance caused by obesity. (Fan et al., 2014) [199]
Reactivity to GABA receptor of drugs and ethanol at low concentrations is enhanced in midkine deficient mice (Vicente-Rodriguez et al., 2014) [200]
MIdkine has therapeutic effects on osteoarthritis in mice. (Xu et al., 2014) [201]

▲up

2015

Anti-midkine antibody exhibits therapeutic effects in a model of hypertension caused by failed kidney function.（Sato et al., 2015）[202]
Transcriptional factor SP1 promotes the growth of glioma cells by enhancing midkine expression. (Luo et al., 2015) [203]
Midkine lacking 40 amino acids in the C-terminal region suppresses neuroblastoma growth. (Dianat et al., 2015) [204]
Lung fibrosis induced by mechanical stress is diminished in midkine deficient mice. (Zhang et al., 2015) [205]
Ethanol activates the midkine-ALK signaling system in the brain. (He et al., 2015) [206]

▲up

2016

An antibody to midkine enhances healing of bone fracture. (Haffner-Luntzer et al., 2016) [207]

▲up