Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified four overlapping genomic DNA clones coding for human class 1 heparin-binding growth factor (HBGF-1), also known as acidic fibroblast growth factor, by screening genomic DNA libraries with an HBGF-1 cDNA probe. The exon-intron structure of the HBGF-1 gene was determined by Southern hybridization and nucleotide sequence analysis. The complete amino acid sequence of human HBGF-1 was deduced from the nucleotide sequence of these genomic DNA clones. The predicted amino acid sequence is identical to the published amino acid sequence determined by protein sequencing. Southern blot analysis of human DNA suggested that there is a single-copy gene coding for HBGF-1. A 4.5-kilobase mRNA and two minor species (3.4 and 2.0 kilobases) homologous to the HBGF-1 gene were detected in cellular RNA isolated from human adult brain and kidney. The HBGF-1 mRNAs from brain and kidney had slightly different sizes. The mechanism for the synthesis of different sizes of mRNA was not determined. We also detected HBGF-1 transcript from glioblastoma cells, fetal brain, and kidney but not from placenta or fetal liver. Since HBGF-1 is an angiogenic factor, these data suggest that it may play a role in embryonic angiogenesis during fetal development.
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PMID:Cloning of the gene coding for human class 1 heparin-binding growth factor and its expression in fetal tissues. 247 53

Midkine (MK), a member of a new family of neurotrophic and angiogenic growth factors whose expression is developmentally regulated, is produced in fetal astrocytes. Malignant astrocytomas, one of the most neovascularized tumors, are derived from astrocytes. There has been no investigation of the expression of MK in human astrocytic tumors. To determine if increased levels of MK expression correlate with the progression of human astrocytomas, we examined surgical specimens of astrocytic tumors of various grades using Northern and Western blotting. MK mRNA and protein expression levels were higher in high-grade astrocytomas (anaplastic astrocytomas and glioblastomas) than in low-grade astrocytomas. As shown by in situ hybridization, MK mRNA expression was intense in a majority of glioblastoma cells but was weak in a small number of low-grade astrocytoma cells. These findings suggest that MK expression correlates with the malignant progression of astrocytomas. The aberrant MK expression in high-grade astrocytomas may underlie their rapid growth and well-vascularized features.
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PMID:Increased expression of midkine during the progression of human astrocytomas. 932 32

Midkine (MK) is a developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN). To investigate the potential role of MK in tumor growth, we expressed MK in human SW-13 cells and studied receptor binding, signal transduction, and activity of MK. The MK protein stimulates soft agar colony formation in vitro and tumor growth of SW-13 cells in athymic nude mice, as well as proliferation of human endothelial cells from brain microvasculature and umbilical vein (HUVEC) in the low ng/ml range. MK binds to anaplastic lymphoma kinase (ALK), the receptor for PTN, with an apparent K(d) of 170 pm in intact cells, and this receptor binding of MK is competed by PTN with an apparent K(d) of approximately 20 pm. Monoclonal antibodies raised against the extracellular ligand-binding domain of ALK inhibit ALK receptor binding of MK as well as MK-stimulated colony formation of SW-13 cells. Furthermore, MK stimulates ALK phosphorylation in WI-38 human fibroblasts and activates PI3-kinase and MAP kinase signal transduction in WI-38, HUVEC, neuroblastoma (SH SY-5Y) and glioblastoma (U87MG) cells that express the ALK protein. We conclude that MK can act as a growth, survival, and angiogenic factor during tumorigenesis and signals through the ALK receptor.
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PMID:Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. 1212 9

Glioblastoma is the most common primary brain tumor in human adults. Since existing treatments are not effective enough, novel therapeutic targets must be sought. The heparin-binding growth factor, heparin affin regulatory peptide (HARP), also known as pleiotrophin (PTN), could potentially represent such a target. We have previously shown that a mutant protein, HARPDelta111-136, which lacks HARP's C-terminal 26 amino acids, acts as a dominant negative HARP effector by heterodimerizing with the wild-type growth factor. The aim of our study was to evaluate the potential inhibitory activity of HARPDelta111-136 on the U87 MG human glioblastoma cell line. By overexpressing the truncated form of HARP in stably established clones of U87 MG cells, we observed an inhibition of proliferation under both anchorage-dependent and anchorage-independent conditions. We confirmed these results in an in vivo subcutaneous tumor xenograft model. In addition, we found that HARPDelta111-136 inhibited cell proliferation in a paracrine manner. Analysis of key cellular pathways revealed a decrease of cell adhesion in U87 MG cells that overexpressed the mutant protein, which could explain this inhibitory effect. A replication-defective adenovirus model that encoded HARPDelta111-136 supported a putative antiproliferative role for the truncated protein in vitro and in vivo. Interestingly, HARPDelta111-136 was also able to abolish angiogenic activity in HUVEC proliferation and in a Matrigel plug assay. These results demonstrate that considering its antiproliferative and angiostatic effects, HARPDelta111-136 could be of great interest when used in conjunction with standard treatments.
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PMID:Antitumorigenic effects of a mutant of the heparin affin regulatory peptide on the U87 MG glioblastoma cell line. 2001 8

Midkine (MK) is a heparin-binding cytokine, and promotes growth, survival, migration and other activities of target cells. After describing the general properties of MK, this review focuses on MK and MK inhibitors as therapeutics for diseases in the central nervous system. MK is strongly expressed during embryogenesis especially at the midgestation period, but is expressed only at restricted sites in adults. MK expression is induced upon tissue injury such as ischemic brain damage. Since exogenously administered MK or the gene transfer of MK suppresses neuronal cell death in experimental systems, MK has the potential to treat cerebral infarction. MK might become important also in the treatment of neurodegenerative diseases such as Alzheimer's disease. MK is involved in inflammatory diseases by enhancing migration of leukocytes, inducing chemokine production and suppressing regulatory T cells. Since an aptamer to MK suppresses experimental autoimmune encephalitis, MK inhibitors are promising for the treatment of multiple sclerosis. MK is overexpressed in most malignant tumors including glioblastoma, and is involved in tumor invasion. MK inhibitors may be of value in the treatment of glioblastoma. Furthermore, an oncolytic adenovirus, whose replication is under the control of the MK promoter, inhibits the growth of glioblastoma xenografts. MK inhibitors under development include antibodies, aptamers, glycosaminoglycans, peptides and low molecular weight compounds. siRNA and antisense oligoDNA have proved effective against malignant tumors and inflammatory diseases in experimental systems. Practical information concerning the development of MK and MK inhibitors as therapeutics is described in the final part of the review.
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PMID:Midkine: a promising molecule for drug development to treat diseases of the central nervous system. 2137 88

Glioblastoma (GBM) is one of the most aggressive forms of cancer. It has been proposed that the presence within these tumors of a population of cells with stem-like features termed Glioma Initiating Cells (GICs) is responsible for the relapses that take place in the patients with this disease. Targeting this cell population is therefore an issue of great therapeutic interest in neuro-oncology. We had previously found that the neurotrophic factor MIDKINE (MDK) promotes resistance to glioma cell death. The main objective of this work is therefore investigating the role of MDK in the regulation of GICs. Methods: Assays of gene and protein expression, self-renewal capacity, autophagy and apoptosis in cultures of GICs derived from GBM samples subjected to different treatments. Analysis of the growth of GICs-derived xenografts generated in mice upon blockade of the MDK and its receptor the ALK receptor tyrosine kinase (ALK) upon exposure to different treatments. Results: Genetic or pharmacological inhibition of MDK or ALK decreases the self-renewal and tumorigenic capacity of GICs via the autophagic degradation of the transcription factor SOX9. Blockade of the MDK/ALK axis in combination with temozolomide depletes the population of GICs in vitro and has a potent anticancer activity in xenografts derived from GICs. Conclusions: The MDK/ALK axis regulates the self-renewal capacity of GICs by controlling the autophagic degradation of the transcription factor SOX9. Inhibition of the MDK/ALK axis may be a therapeutic strategy to target GICs in GBM patients.
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PMID:Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells. 3230 72