Wnt Signaling Inhibitor Comprising Insulin-Like Growth Factor-Binding Protein

a technology of growth factor and inhibitor, which is applied in the direction of peptide/protein ingredients, cell culture active agents, dna/rna fragmentation, etc., can solve the problems of little findings on the detailed mechanism of such igf-independent actions of igfbps, and achieve the effect of enhancing wnt signalling and preventing and/or treating

Inactive Publication Date: 2011-10-06
CHIBA UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0052]According to the present invention, there can be provided the inhibitor of Wnt signalling, comprising as an active ingredient an insulin-like growth-factor-binding protein (IGFBP), the protein binding to a Wnt receptor, and / or a polynucleotide encoding the protein.
[0053]Wnt signals are involved in the control of morphogenesis and are important for various phenomena such as development, differentiation control, growth regulation, and survival of stem cells, and cell malignant transformation. The inhibitor of Wnt signalling according to the present invention is therefore useful as a medicament that modulates morphogenesis and cell proliferation, such as cardiac development and / or cardiomyocyte differentiation, in the fields of pharmaceutical development, scientific research, and the like.
[0054]According to the present invention, there can also be provided the medicament for the prevention and / or treatment of a disease due to enhanced Wnt signalling and the medicament for the induction of cardiomyocyte differentiation, the medicaments each comprising as an active ingredient the protein and / or a polynucleotide encoding the protein. The present invention can also provide the use of an insulin-like growth-factor-binding protein (IGFBP), the protein binding to a Wnt receptor, and / or a polynucleotide encoding the protein, in the manufacture of an inhibitor of Wnt signalling, a medicament for the prevention and / or treatment of a disease due to enhanced Wnt signalling, and a medicament for the induction of cardiomyocyte differentiation. The present invention can also provide the use of an insulin-like growth-factor-binding protein (IGFBP), the protein binding to a Wnt receptor, and / or a polynucleotide encoding the protein, in the inhibition of Wnt signalling, the prevention and / or treatment of a disease due to enhanced Wnt signalling, and the induction of cardiomyocyte differentiation. According to the present invention, there can also be provided the method of inhibiting Wnt signalling, comprising using an insulin-like growth-factor-binding protein (IGFBP), the protein binding to a Wnt receptor, and / or a polynucleotide encoding the protein, the method for the prevention and / or treatment of a disease due to enhanced Wnt signalling, the method of inducing cardiomyocyte differentiation, and the cardiomyocyte which is obtained by the method of inducing cardiomyocyte differentiation and the use thereof.

Problems solved by technology

However, there are little findings on detailed mechanisms of such IGF-independent actions of IGFBPs (Non-Patent References 9 and 10).

Method used

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  • Wnt Signaling Inhibitor Comprising Insulin-Like Growth Factor-Binding Protein
  • Wnt Signaling Inhibitor Comprising Insulin-Like Growth Factor-Binding Protein
  • Wnt Signaling Inhibitor Comprising Insulin-Like Growth Factor-Binding Protein

Examples

Experimental program
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Effect test

example 1

[1] Materials and Methods

(Plasmids and Reagents)

[0163]Mouse IGFBP and Xenopus IGFBP-4 (hereinafter, sometimes abbreviated as XIGFBP-4) cDNA clones were purchased from Open Biosystmes. A mutant (XIGFBP-4-H74P) in which the 74th histidine (His) is replaced by proline (Pro) in XIGFBP-4 was produced by a QuikChange (registered trademark) Site-Directed Mutagenesis kit (manufactured by Stratagene). Such mutant does not bind to IGFs. His-tagged human wild-type IGFBP-4 and mutant IGFBP-4-H74P (Qin, X., Strong, D. D., Baylink, D. J. & Mohan, S., Structure-function analysis of the human insulin-like growth factor binding protein-4., J Biol Chem 273, 23509-16 (1998)) were produced using a HitTrap HP kit (manufactured by Amersham) and then purified.

[0164]Soluble forms of LRP6 deletion mutants and probes for in situ hybridization analysis (Nkx2.5, cTnI, and Hex) were generated by PCR. IGFBP-4, Wnt3A, IGF-I, IGF-II, and BMP2 were purchased from R&D. Neutralizing antibodies were purchased from R&D...

example 2

[0213]IGFBPs comprise six members, i.e., IGFBP-1 to IGFBP-6. Wnt signalling inhibitory actions of those IGFBP family members were examined by reporter gene assays and β-catenin stabilization assays. Further, the interactions between each of the IGFBP family members with LRP6 or Frz8 were examined by IP / western analyses. The reporter gene assays, β-catenin stabilization assays, and IP / western analyses were performed by the same methods as those described in Example 1.

[0214]Among the IGFBP family members, IGFBP-4 most strongly inhibited Wnt3A-induced β-catenin expression. It was revealed that IGFBP-1, IGFBP-2, and IGFBP-6 also exhibited moderate Wnt inhibitory activities, whereas IGFBP-3 and IGFBP-5 did not exhibit such activities (FIG. 9-a to FIG. 9-c). Consistent with the results, the IP / western analyses revealed that IGFBP-1, IGFBP-2, IGFBP-4, and IGFBP-6 interacted with LRP6 or Frz8CRD, whereas IGFBP-3 and IGFBP-5 did not interact with LRP6 or Frz8CRD (FIG. 9-d and FIG. 9-e).

[0215...

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Abstract

Provided is a novel soluble factor that modulates morphogenesis and cell proliferation, such as cardiac development and / or cardiomyocyte differentiation. Specifically provided are: an inhibitor of Wnt signalling, comprising an insulin-like growth-factor-binding protein (IGFBP), the protein being binding to a Wnt receptor, and / or a polynucleotide encoding the protein; a medicament for prevention and / or treatment of a disease due to enhanced Wnt signalling, comprising the inhibitor of Wnt signalling, and a medicament for induction of cardiomyocyte differentiation; and a method for prevention and / or treatment of a disease due to enhanced Wnt signalling and a method of inducing cardiomyocyte differentiation, the methods each comprising using the inhibitor of Wnt signalling, and a cardiomyocyte, which is obtained by the method of inducing cardiomyocyte differentiation, and a use thereof.

Description

TECHNICAL FIELD[0001]The present invention relates to an inhibitor of Wnt signalling, comprising an insulin-like growth-factor-binding protein (hereinafter, sometimes abbreviated as IGFBP). The present invention also relates to an inhibitor of Wnt signalling, comprising a polynucleotide encoding IGFBP. The present invention also relates to a method of inhibiting Wnt signalling, comprising using IGFBP. The present invention also relates to a method of inhibiting Wnt signalling, comprising using a polynucleotide encoding IGFBP. The present invention also relates to a use of IGFBP and / or a polynucleotide encoding IGFBP in the manufacture of an inhibitor of Wnt signalling. The present invention also relates to a medicament for the prevention and / or treatment of a disease due to enhanced Wnt signalling, comprising the inhibitor of Wnt signalling. The present invention also relates to a method for the prevention and / or treatment of a disease due to enhanced Wnt signalling, comprising admi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/34C07K14/47C07H21/00C07H21/04A61K38/17A61K31/7088C12N5/077A61P9/00A61K38/00A61K38/02A61K48/00A61P9/04C12N15/09C12N15/113
CPCA61K31/7088A61K38/00A61K48/005C12N2310/14C12N15/113C12N15/1138C07K14/4743A61P9/00A61P9/04A61K38/1754C12N5/0693C12N2501/105
Inventor KOMURO, ISSEISHIOJIMA, ICHIROZHU, WEIDONG
Owner CHIBA UNIVERSITY
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