Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcripts for the alpha 1 chain of mouse type XVIII collagen were found to be heterogeneous at their 5'-ends and to encode three variant N-terminal sequences of the ensuing 1315-, 1527-, or 1774-residue collagen chains. The variant mRNAs appeared to originate from the use of two alternate promoters of the alpha 1(XVIII) chain gene, resulting in the synthesis of either short or long N-terminal non-collagenous NC1 domains, the latter being further subject to modification due to alternative splicing of the transcripts. As a result, the 1527- and 1774-residue polypeptides share the same signal peptide, and the lengths of their NC1 domains are 517 or 764 amino acid residues, respectively, while the 1315-residue polypeptide has a different signal peptide and a 301-residue NC1 domain. The longest NC1 domain was strikingly characterized by a 110-residue sequence with 10 cysteines, which was found to be homologous with the previously identified frizzled proteins belonging to the family of G-protein-coupled membrane receptors. Thus, it is proposed that the cysteine-rich motif, termed fz, represents a new sequence motif that can be found in otherwise unrelated proteins. Tissues containing mainly one or two NC1 domain mRNA variants or all three NC1 domains were identified, indicating that there is tissue-specific utilization of two alternate promoters and alternative splicing of alpha 1(XVIII) transcripts.
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PMID:Identification of three N-terminal ends of type XVIII collagen chains and tissue-specific differences in the expression of the corresponding transcripts. The longest form contains a novel motif homologous to rat and Drosophila frizzled proteins. 787 42

We report on the isolation of mouse cDNA clones which encode a collagenous sequence designated here as the alpha 1 chain of type XVIII collagen. The overlapping clones cover 2.8 kilobases and encode an open reading frame of 928 amino acid residues comprising a putative signal peptide of 25 residues, an amino-terminal noncollagenous domain of 301 residues, and a primarily collagenous stretch of 602 residues. The clones do not cover the carboxyl-terminal end of the polypeptide, since the translation stop codon is absent. Characteristic of the deduced polypeptide is the possession of eight noncollagenous interruptions varying in length from 10 to 24 residues in the collagenous amino acid sequence. Other features include the presence of several putative sites for both N-linked glycosylation and O-linked glycosaminoglycan attachment and homology of the amino-terminal noncollagenous domain with thrombospondin. It is of particular interest that five of the eight collagenous sequences of type XVIII show homology to the previously reported type XV collagen, suggesting that the two form a distinct subgroup among the diverse family of collagens. Northern blot hybridization analysis revealed a striking tissue distribution for type XVIII collagen mRNAs, as the clones hybridized strongly with mRNAs of 4.3 and 5.3 kilobases that were present only in lung and liver of the eight mouse tissues studied.
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PMID:Alpha 1(XVIII), a collagen chain with frequent interruptions in the collagenous sequence, a distinct tissue distribution, and homology with type XV collagen. 818 94

The mouse gene for the alpha 1 chain of type XVIII collagen (Col18a1) is more than 102 kb and consists of 43 exons. Type XVIII collagen transcripts encode polypeptides that differ with respect to three variant N-terminal noncollagenous domains that are 301 (NC1-301), 517 (NC1-517), or 764 (NC1-764) residues in length. Characterization of genomic clones revealed that the three variant NC1 domains result from the use of two alternative promoters, separated by a distance of 50 kb. The upstream promoter, promoter 1, directs the synthesis of the NC1-301 domain in conjunction with exons 1 and 2, whereas the downstream promoter, promoter 2, directs that of the NC1-517 and NC1-764 domains in conjunction with exon 3, with the latter two variants differing with respect to alternative splicing of the exon 3 sequences. Exons 4-9 encode a portion of the NC1 domain shared by all three polypeptide variants, and exons 9-43 encode the common collagenous and C-terminal noncollagenous sequences. The marked differences previously observed in the expression of variant type XVIII collagen transcripts in mouse tissues thus result from tissue-specific use of these two promoters.
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PMID:Characterization of the mouse gene for the alpha 1 chain of type XVIII collagen (Col18a1) reveals that the three variant N-terminal polypeptide forms are transcribed from two widely separated promoters. 883 8

Gene therapy transfer of angiostatin and endostatin represents an alternative method of delivering angiogenic polypeptide inhibitors. We examined whether liposomes complexed to plasmids encoding angiostatin or endostatin inhibited angiogenesis and the growth of MDA-MB-435 tumors implanted in the mammary fat pads of nude mice. We determined that plasmids expressing angiostatin (PCI-Angio) or endostatin (PCI-Endo) effectively reduced angiogenesis using an in vivo Matrigel assay. We then investigated the efficacy of these plasmids in reducing the size of tumors implanted in the mammary fat pad of nude mice. Both PCI-Angio and PCI-Endo significantly reduced tumor size when injected intratumorally (P < 0.05). Compared to the untreated control group, the mice treated with PCI-Angio and PCI-Endo exhibited a reduction in tumor size of 36% and 49%, respectively. In addition, we found that i.v. injections of liposomes complexed to PCI-Endo reduced tumor growth in the nude mice by nearly 40% when compared to either empty vector (PCI) or untreated controls (P < 0.05). These findings provide a basis for the further development of nonviral delivery of antiangiogenic genes.
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PMID:Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. 1072 14

Circulating elongated forms of the angiogenesis inhibitor and potential anti-cancer drug endostatin were isolated from human blood filtrate. Immunoreactive endostatin was identified by a polyclonal rabbit antiserum raised against an N-terminal epitope of the polypeptide and purified by consecutive chromatographic steps and immunoblotting. N- and C-terminal sequence analyses of the isolated molecules revealed different forms of endostatin starting with V(117)HLRPAR. lacking the last and final three residues of the noncollagenous domain 1 (NC-1) of collagen XVIII, respectively. These polypetides are found to be O-glycosylated at T(125) (residue 9) with a glycan structure of the mucin type consisting of galactose N-acetylgalactosamine and N-acetylneuraminic acid residues. Carbohydrate analyses were performed via the semiquantitative HPLC-electrospray ionization mass spectrometry (ESMS) technique after exoglycosidase hydrolysis. Circulating endostatins are present as sialoglycoprotein (22 000 and 21 841 Da +/- 0.02%) and asialoglycoprotein structures (21 710 and 21 549 Da +/- 0.02%), while the two completely deglycosylated forms are obtained only after enzymatic incubation. The described glycosylated endostatins may represent intermediates in the proteolytic pathway of the NC-1 domain of collagen XVIII resulting in bioactive endostatins. Furthermore, immunoreactive endostatin-related C-terminal fragments of human collagen XV are found in the hemofiltrate. These polypeptides exhibit the N-terminal sequences P(66)HLLPPP. and Y(81)EKPALH. of the collagen XV NC-1 domain. ESMS and immunoblotting analyses reveal three glycosylated polypeptides with a molecular mass ranging from 16 to 21 kDa. Due to the high degree of homology between collagen XV and collagen XVIII as well as their analoqous proteolytic processing, functional similarities of collagen XVIII- and XV-related fragments should be revealed in future experiments.
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PMID:Novel glycosylated forms of human plasma endostatin and circulating endostatin-related fragments of collagen XV. 1044 Nov 14

The collagen superfamily of proteins plays a dominant role in maintaining the integrity of various tissues and also has a number of other important functions. The superfamily now includes more than 20 collagen types with altogether at least 38 distinct polypeptide chains, and more than 15 additional proteins that have collagen-like domains. Most collagens form polymeric assemblies, such as fibrils, networks and filaments, and the superfamily can be divided into several families based on these assemblies and other features. All collagens also contain noncollagenous domains, and many of these have important functions that are distinct from those of the collagen domains. Major interest has been focused on endostatin, a fragment released from type XVIII collagen, which potently inhibits angiogenesis and tumour growth. Collagen synthesis requires eight specific post-translational enzymes, some of which are attractive targets for the development of drugs to inhibit collagen accumulation in fibrotic diseases. The critical roles of collagens have been clearly illustrated by the wide spectrum of diseases caused by the more than 1,000 mutations that have thus far been identified in 22 genes for 12 out of the more than 20 collagen types. These diseases include osteogenesis imperfecta, many chondrodysplasias, several subtypes of the Ehlers-Danlos syndrome, Alport syndrome, Bethlem myopathy, certain subtypes of epidermolysis bullosa, Knobloch syndrome and also some cases of osteoporosis, arterial aneurysms, osteoarthrosis, and intervertebral disc disease. The characterization of mutations in additional collagen genes will probably add further diseases to this list. Mice with genetically engineered collagen mutations have proved valuable for defining the functions of various collagens and for studying many aspects of the related diseases.
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PMID:Collagens and collagen-related diseases. 1131 Sep 42

Human type XVIII collagen was found to be expressed as three variants, termed NC1-303, NC1-493 and NC1-728, differing in their N-terminal non-collagenous domains (NC1). The corresponding gene was found to be approximately 105 kb in size and contain 43 exons. The short variant is derived from utilization of an upstream promoter associated with the first two exons of the gene. The two other variants are derived from a downstream promoter and alternative splicing of exon 3, resulting in 192 residues of shared sequences characterized by a putative approximately 30 residue conserved coiled-coil motif and 235 residues of sequences specific to NC1-728. The NC1-728 variant has a conserved cysteine-rich domain homologous with the ligand-binding part of the frizzled proteins. A polyclonal antibody specific to the NC1-728 variant was generated, and immunostaining of fetal tissues revealed staining in lung and skeletal muscle. Human serum contained 173- and 144-kDa alpha1(XVIII) chains corresponding to the NC1-728 and NC1-493 variants, respectively. A 200-kDa polypeptide was detected in cells transfected with a cDNA construct corresponding to the full-length NC1-728 variant, and EBNA-293 cells endogenously synthesizing low amounts of type XVIII collagen had a 45-kDa fragment in their culture medium that corresponded to most of the NC1 domain of the NC1-728 variant, suggesting processing of the N-terminal frizzled-containing domain.
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PMID:Characterization of the human type XVIII collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif. 1461 89

Endostatin is a potent angiogenesis inhibitor. The structure of endostatin is unique in that its secondary structure is mainly irregular loops and beta-sheets and contains only a small fraction of alpha-helices with two pairs of disulfide bonds in a nested pattern. We choose human endostatin as a model system to study the folding mechanism of this kind. Nuclear magnetic resonance (NMR), tryptophan emission fluorescence, and circular dichroism (CD) were used to monitor the unfolding process of endostatin upon acid titration. Urea-induced unfolding was used to measure the stability of endostatin under different conditions. Our results show that endostatin is very acid-resistant; some native structure still remains even at pH 2 as evidenced by (1)H NMR. Trifluoroethanol (TFE) destabilizes native endostatin, while it makes endostatin even more acid-resistant in the low pH region. Stability measurement of endostatin suggests that endostatin is still in native structure at pH 3.5 despite the decreased stability. Acid-induced unfolding of endostatin is reversible, although it requires a long time to reach equilibrium below pH 3. Surprisingly, the alpha-helical content of endostatin is increased when it is unfolded at pH 1.6, and the alpha-helical content of the polypeptide chain of unfolded endostatin increases linearly with TFE concentration in the range of 0-30%. This observation indicates that the polypeptide chain of unfolded endostatin has an intrinsic alpha-helical propensity. Our discoveries may provide clues for refolding endostatin more efficiently. The acid-resistance property of endostatin may have biological significance in that it cannot be easily digested by proteases in an acidic environment such as in a lysosome in the cell.
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PMID:Acid-induced unfolding mechanism of recombinant human endostatin. 1499 92

Tumor growth requires proteolytic activity. As a consequence, protein breakdown products are present in the circulation of patients with cancer. Within the past decade a large number of proteolytic fragments have been identified that inhibit angiogenesis and tumor growth. The mechanism of action of these inhibitors is still poorly understood. We recently found that the effects of the angiogenesis inhibitor endostatin on endothelial cells is critically dependent on the presence of cross-beta structure, a structure also present in amyloidogenic polypeptides in plaques of patients with amyloidosis, such as Alzheimer disease. We also showed that cross-beta structure containing endostatin is a ligand for tissue-type plasminogen activator (tPA). We noted that many angiogenesis inhibitors stimulate tPA-mediated plasminogen activation. Because the presence of cross-beta structure is the common denominator in tPA-binding ligands, we hypothesize that these endogenous antiangiogenic proteolytic fragments share features with amyloidogenic polypeptides. We postulate that the cross-beta structural fold is present in these antiangiogenic polypeptide fragments and that this structure mediates the inhibitory effects. The hypothesis provides new insights in the potential mechanisms of these angiogenesis inhibitors and offers opportunities to improve their use.
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PMID:Do antiangiogenic protein fragments have amyloid properties? 1516 35

Endostatin can inhibit the proliferation and migration of endothelial cells. It contains two pairs of disulfide bonds in a nested pattern. We constructed three mutants, C33A/C173A, C135A/C165A, and all-Ala, to evaluate the contributions of individual disulfide bonds to the structure, stability, and biological functions of endostatin. Both tryptophan emission fluorescence spectrum and 1H nuclear magnetic resonance spectrum show that C135A/C165A and all-Ala, the two mutants lacking disulfide bond Cys135-Cys165, lost nearly their entire tertiary structure. Although C33A/C173A appears to retain some native-like structures, it is less stable and has a higher helical content, which confirms our earlier hypothesis that the polypeptide backbone of endostatin has a high helical propensity. C135A/C165A and all-Ala mutants lost most of their inhibitory activities both on the migration and proliferation of human microvascular endothelial cells, whereas C33A/C173A is partially active. The mutants without disulfide bond Cys135-Cys165 can hardly be internalized and localized to cytoskeleton and nucleus in the cell, which probably contributes to their loss of inhibition on the migration and proliferation of endothelial cells. Our studies provide a structural basis for the two disulfide bonds on the biological functions of endostatin.
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PMID:Contributions of disulfide bonds in a nested pattern to the structure, stability, and biological functions of endostatin. 1563 76


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