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Novel agent for inducing apoptosis comprising Msx1 or a gene encoding the same as an active ingredient

Inactive Publication Date: 2007-01-25
RES & BUSINESS FOUNDATION SUNGKYUNKWAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014] The present invention has been made in an effort to provide therapy that is capable of effectively modulating apoptosis in tissues such as in tumors where the induction of apoptosis is desirable. The present inventors have discovered that Msx1 can effectively induce apoptosis in cells or tissues where the apoptosis is prevented from occurring due to an inactivation of p53 protein or absence of p53 protein.
[0019] In a further aspect, said interaction of Msx1 or homeodomain thereof with p53 protein leads to increased stability, and / or nuclear localization of p53, which is a clear implication for modulation of apoptosis by Msx1 via control of p53.

Problems solved by technology

In particular, the ability to undergo apoptosis is closely associated with cancer development in that a reduction in such apoptotic ability would result in the retention of cells with unrepaired DNA damage and a consequent increased risk of mutations, which may lead to development of cancer.

Method used

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  • Novel agent for inducing apoptosis comprising Msx1 or a gene encoding the same as an active ingredient
  • Novel agent for inducing apoptosis comprising Msx1 or a gene encoding the same as an active ingredient
  • Novel agent for inducing apoptosis comprising Msx1 or a gene encoding the same as an active ingredient

Examples

Experimental program
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example 1

Construction of Various Expression Vectors

[0078] Various viral and non-viral vectors containing Msx1 or various deletion products thereof as in FIG. 3A, or containing p53, were constructed and used to investigate the activity of Msx1 of the present invention as previously described (Park et al., Cancer Res. 65: 749-757, 2005; Hwang et al., Int. J. Gynecol. Cancer 8: 27-36, 1998).

[0079] Adenoviral Vectors

[0080] Briefly, for viral constructs, adenoviral expression systems were used. An adenoviral vector pΔACMVMsx1(Ad-Msx1) encoding Msx1 was prepared by subcloning 0.9 kb of an Msx1 fragment of human origin into a BamHI site in multicloning sites of pΔACMVp(A). An adenoviral vector Ad-p53 encoding p53 was prepared as previously described (Hwang et al., Int. J. Gynecol. Cancer 8: 27-36, 1998). For the production of replication deficient adenoviruses, adenoviral constructs as described above and pJM17 carrying adenoviral genomic DNA (F. Graham, McMaster University, Ontario, Canada) wer...

example 2

Cell Culture and Transfection

[0086] Cervical cancer cell line HeLa ((American Type Culture Collection, USA), Human lung cancer cell line H1299 (American Type Culture Collection, USA), and HEK 293 (Clonetics, San Diego, Calif., USA) were cultured as described (Lee et al., Oncogene (2001) 20:6700-6776; Park et al, ibid). Briefly, the HeLa, H1299, and HEK 293 cells were cultured in DMEM (Dulbecco's Modification of Eagles Medium) and EMEM (Eagles Minimum Essential Medium), respectively, each supplemented with 10% FBS and antibiotics (Life Technologies, Gaithersburg, Md., USA). The cells were incubated at 37□ in a 5% CO2 / 95% air atmosphere.

[0087] DNA transfection into each of the above cell lines and adenoviral infection were carried out as described (Lee et al., Oncogene (2001) 20:6700-6776; Park et al., ibid).

example 3

The Apoptosis Inducing Activity of Msx1

[0088] The activity of Msx1 for inducing apoptosis was investigated as described (Park et al., ibid). Briefly, HeLa cells were seeded onto each well of 4-chamber slides (Nalgene Nunc, Rochester N.Y., USA) at 5×104 cells / well and then transfected with pEGFP / full length Msx1 and empty pEGFP vectors as prepared in Example 1 for 24 hours using Effectene™ (Qiagen, Hilden, Germany) as recommended by the manufacturer.

[0089] The transfected HeLa cells were then tested for apoptosis by morphologic alterations of whole cells using a light microscope (Zeiss, Hallbergmoos, Germany) as well as the nucleus, and by cell growth inhibition using an MTT colorimetric assay and FACS analysis as described (Park et al., ibid).

[0090]FIGS. 1A to 1D illustrate the Msx1-mediated induction of apoptosis in HeLa cells after the expression of a full length Msx1 gene (full Msx1 vector). As a control, cells containing only the vector without the Msx1 gene were used (contro...

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Abstract

The present invention relates to a novel use of Msx1 protein or a nucleotide encoding the same for inducing apoptosis. The Msx1 of the present invention induces apoptosis through direct interaction with p53 via a homeodomain and such interaction leads to increased stability, and / or nuclear localization of p53 in cells. The Msx1 or homeodomain thereof can be effectively used for the treatment of tumors, in which wild-type p53 protein has lost its function by some mechanism that inactivates p53 proteins.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority to and the benefit of Korean Patent Application No. 10-2005-66541 filed in the Korean Industrial Property Office on Jul. 22, 2005, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates to a novel use of Msx1 protein and nucleic acids encoding the same for modulating apoptosis. Particularly, the present invention relates to compositions for modulating apoptosis using Msx1 or nucleic acids encoding the same and use thereof in the treatment of disease states associated with abnormal apoptosis. BACKGROUND OF THE INVENTION [0003] Apoptosis, also called programmed cell death, is a form of cell death in which a series of programmed events leads to the destruction of cells (Kerr et al., British Journal of Cancer, 26: 239-257, 1972). Apoptosis plays an important role in an organism by controlling the normal development and providing a defense agains...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K38/17
CPCA61K48/005A61K38/1709A61P35/00C07K14/435C12N9/00
Inventor LEE, JE-HOPARK, KYOUNGSOOK
Owner RES & BUSINESS FOUNDATION SUNGKYUNKWAN UNIV
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