Disease relevance of MDK

• The growth factor midkine (MK) is a cytokine that inhibits the attachment of human immunodeficiency virus particles by a mechanism similar to the nucleolin binding HB-19 pseudopeptide [1].
• We examined the expression level of the midkine (MK) and c-erbB-2 genes in both tumorous and matched nontumorous specimens from 18 patients with breast cancer [2].
• Transfection of breast cancer cells with either the MK promoter- or the c-erbB-2 promoter-linked herpes simplex virus thymidine kinase gene increased their sensitivity to the prodrug ganciclovir [2].
• Amphiregulin-associated protein: complete amino acid sequence of a protein produced by the 12-0-tetradecanoylphorbol-13-acetate-treated human breast adenocarcinoma cell line MCF-7 [3].
• BACKGROUND: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis [4].

Psychiatry related information on MDK

• In addition, deposits of MK and/or PTN are found in neurodegenerative diseases, such as Alzheimer's disease and multiple system atrophy [5].

High impact information on MDK

• The dimer has a fused heparin-binding site at the dimer interface of the C-terminal domain, and the heparin-binding sites on MK fit the sulfate group clusters on heparin [6].
• The MK dimer has been shown to be the active form, giving signals to endothelial cells and probably to neuronal cells [6].
• Midkine (MK) is a 13 kDa heparin-binding polypeptide which enhances neurite outgrowth, neuronal cell survival and plasminogen activator activity [6].
• This protein and a second 29-kDa protein (pI 6.0) were labeled by MDK, but excess unlabeled methoprene or MDK only prevented binding to the latter [7].
• Purified KAF stimulated the growth of normal human keratinocytes, mouse AKR-2B cells, and a mouse keratinocyte cell line (BALB/MK) [8].

Chemical compound and disease context of MDK

• The growth factor midkine (MK) has been reported to bind heparan sulfate and nucleolin, two components of the cell surface implicated in the attachment of HIV-1 particles [9].
• In contrast, the appican CS from SH-SY5Y neuroblastoma cells contained no E disaccharide and showed no binding to either MK or PTN [10].
• In this study, the appican CS chain from rat C6 glioma cells was shown to specifically bind several growth/differentiation factors including midkine (MK) and pleiotrophin (PTN) [10].
• Substratum-bound MK or poly-L-lysine induced cell adhesion of N2a neuroblastoma cells, while only MK promoted neurite outgrowth of these cells [11].
• Among these, midkine (MDK), a heparin-binding growth factor, was overexpressed in all drug-resistant cell lines, strongly suggesting that MDK might contribute to multidrug resistance in gastric cancer cells [12].

Biological context of MDK

• HB-19 prevents the binding of MK to the low affinity binding site only [1].
• The use of various deletion constructs of nucleolin then indicated that the extreme C-terminal end of nucleolin, containing repeats of the amino acid motif RGG, is the domain that binds MK [1].
• Regulatory regions of the MK gene were able to activate a reporter gene to a similar degree as those of the c-erbB-2 gene in the human breast cancer cell lines tested [2].
• In contrast, the expression of the MK and c-erbB-2 genes in tumorous specimens was upregulated in 18 and 6 specimens, respectively [2].
• The complete amino acid sequence of ARAP was determined [3].

Anatomical context of MDK

• Midkine (MDK) is a retinoic acid-responsive gene concerned with prenatal development and neurite growth [13].
• Full-length HB-GAM is not a mitogen for Balb/3T3 clone A31, Balb MK, NRK, or human umbilical vein endothelial cells [14].
• RESULTS: Concentrations of midkine (MK) and stem cell factor, but not epidermal growth factor, were substantially increased in serum of NF1 patients when compared with healthy controls [15].
• The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues [4].
• RESULTS: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells [4].

Associations of MDK with chemical compounds

• Midkine (MK) is a heparin-binding growth factor with migration-promoting and survival-promoting activities [16].
• The specific binding of MK to cells is independent of heparan sulfate and chondroitin sulfate expression [1].
• METHODS: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2'-deoxyuridine (BrdU) incorporation [4].
• MK-induced migration of peritoneal exudate macrophages was inhibited by heparin, chondroitin sulfate E and dermatan sulfate, but not by chondroitin sulfate D or chondroitin 6-sulfate [17].
• 3) Gln42 or Gln44 in the N-terminal half and Gln95 in the C-terminal half served as amine acceptors in the cross-linking reaction, as judged from the incorporation of putrescine into whole MK or each half domain, and the competitive inhibition of the cross-linking by MK-derived peptides containing Gln residue(s) [18].

Physical interactions of MDK

• These findings suggest that LRP is a component of the receptor complex for MK [16].
• Midkine (MK) is a heparin-binding growth factor that occurs as a product of the retinoic acid-inducible gene [19].
• MK bound to heparan sulfate chains of glypican-2 in a manner similar to syndecan-3 [11].

Regulatory relationships of MDK

• Confocal immunofluorescence laser microscopy revealed the colocalization of MK and the cell-surface-expressed nucleolin at distinct spots [1].
• This analysis revealed that all normal lung tissues examined (n = 17) expressed PTN but only two expressed MK [20].
• Microbeads coated with MK or poly-L-lysine induced clustering of glypican-2 as well as syndecan-3 [11].
• 4) This peptide abolished the biological activity of MK to enhance the plasminogen activator activity in bovine aortic endothelial cells [18].

Other interactions of MDK

• The dissociation constant of binding between LRP and MK was 3.5 nM [16].
• Our results suggest that the cell surface-expressed nucleolin serves as a low affinity receptor for MK and could be implicated in its entry process [1].
• Stem cell factor and MK concentrations above a defined threshold in serum of NF1 patients are of diagnostic benefit for 96% of patients in the cohort tested [15].
• The apparent dissociation constants for purified ryudocan were as follows: bFGF, 0.50 nM; MK, 0.30 nM; and TFPI, 0.74 nM [21].
• Within the NF1 group, MK levels increased dramatically at puberty from an average of 0.79 ng/mL in patients <18 years to 1.18 ng/mL in patients >18 years old [15].

Analytical, diagnostic and therapeutic context of MDK

• Midkine gene (MDK), a gene for prenatal differentiation and neuroregulation, maps to band 11p11.2 by fluorescence in situ hybridization [13].
• These data showed that the MK promoter activated a therapeutic gene in a wider range of human breast cancer than the c-erbB-2 promoter and suggest that MK promoter-mediated gene therapy is potentially more favorable in clinical settings [2].
• The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RT-PCR [4].
• Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay [4].
• Complementary DNA constructs coding for the mature HBNF and MK proteins were expressed in bacteria and purified by heparin affinity chromatography [22].

References