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Novel use of aim 3 acting as a tumor suppressor

a tumor suppressor and tumor cell technology, applied in the field of tumor suppressors, can solve the problems of insufficient understanding of the biological functions of p18, inability to fully establish the intracellular biochemical mechanism of the signal transduction system where the damage caused by dna damage activates atm/atr, and so as to inhibit the proliferation of tumor cells and promote the phosphorylation of atm/atr

Inactive Publication Date: 2006-03-02
SCHWARZ HERBERT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0068] In another aspect, the present invention provides a method for treating or preventing ATM/ATR-mediated diseases using the AIM3 protein or a nucleic acid encoding the AIM3 protein. Specifically, the present invention provides a method for treating or preventing ATM- or ATR-mediated diseases, which comprise administering to a subject requiring treatment an effective amount of one selected from the group consisting of the following: (a) an isolated polypeptide of an AIM3 protein; (b) a polypeptide having at least 70% homology with the polypeptide (a); and (c) an isolated nucleic acid encoding the polypeptide (a) or (b). As used herein, the term “subject” means mammals, particularly animals including human beings. The subject may be a patient requiring treatment. Furthermore, the term “ATM- or ATR-mediated diseases” refers to diseases induced by the inactivation or activation reduction of ATM/ATR, i.e., diseases induced by abnormalities occurring in signal transduction pathways mediated by ATM/ATR, due to the inactivation or activation reduction of ATM/ATR. The signal transduction pathways mediated by ATM/ATR include signal transduction pathways mediated by ATM/ATR themselves or ATM/ATR-regulated proteins. The signal transduction pathways may be signal transduction pathways in DNA repair, cell cycle regulation, apoptosis, p53 regulation, angiogenesis and/or intracellular stress response. The ATM/ATR-mediated diseases may be caused by the over-proliferation of cells, such as cancers or psoriasis. The cancers include, but are not limited to, breast cancer, rectal cancer, lung cancer, small-cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine carcinoma, ovarian cancer, colorectal cancer, cancer near the anus, colon cancer, oviduct carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulva carcinoma, Hodgkin's disease, esophagus cancer, small intestinal tumor, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft-tissue sarcoma, uterin...

Problems solved by technology

This leads to an increase in the incidence of cancer cells.
In addition, the intracellular biochemical mechanism of a signal transduction system where the DNA damage causes the activation and operation of ATM / ATR was not completely established.
However, the biological functions of p18 are not yet clearly understood, and particularly, there is no study on the relation between p18 and cancer.

Method used

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  • Novel use of aim 3 acting as a tumor suppressor
  • Novel use of aim 3 acting as a tumor suppressor
  • Novel use of aim 3 acting as a tumor suppressor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0184] Generation of AIM3 Gene-deficient Mutant Mice

[0185] The present inventors generated AIM3-deficient mice by a gene trap method (Zambrowicz, B. P. et al., Nature, 392:608-611, 1998). Among the embryonic stem cell library of 129 / SvEvBrd mouse in which the gene trap vector was randomly introduced (OmniBank Library, Lexicon Genetics), the OST377244 clone including AIM3 genes mutated by the integration of the gene trap vectors was found out. Using this clone, C57BL6 / albino AIM3 heterozygous mice were generated following the standard protocol of Lexicon Genetics, Inc. The heterozygous mice were interbred to generate the homozygous offspring.

example 2

[0186] Examination of Genotypic and Phenotypic Characteristics of AIM3 Gene-deficient Mice

[0187] Determination of Site of Gene Trap Vector Insertion in AIM3 Allele

[0188] The site of a gene trap vector insertion in an AIM3 mutant allele was determined by sequencing analysis. Here, the sequencing was performed by Pangenomics, a sequencing company. As shown in FIG. 1a, the sequencing results indicated that the gene trap vector was inserted between exon I and exon II of the AIM3 gene.

[0189] Genomic PCR Analysis

[0190] From the tail of each of the mice generated in , genomic DNA was isolated. Then, about 1.5-kb DNA fragment containing the exon I region of the AIM3 gene was amplified by PCR with a primer pair of p18F-1 and p18R-1 (SEQ ID NO: 3 and SEQ ID NO: 4) (see FIG. 1a). In addition, about 0.8-kb DNA fragment containing a part of the AIM3 gene and a part of the gene trap vector was amplified by PCR with the p18F-1 primer and an LTR primer (SEQ ID NO: 5) binding to the gene trap ve...

example 3

[0203] Examination of Histological Characteristics of AIM3± Mice

[0204] In order to determine the functions of the AIM3 gene, the present inventors isolated tissues and organs from the AIM3± mice and analyzed the histological characteristics of the isolated tissues and organs.

[0205] At first, after sacrifing mice at given time intervals, various tissues were isolated and fixed with 10% formalin. The fixed tissues were embedded in paraffin, followed by subjecting into H&E staining. In order to determine B cell metastasis, immunohistochemical staining for surface marker B220 was performed with paraffin slide. After de-paraffin using xylene, the slide was incubated in a blocking buffer (1:100, 5% BSA and 0.1% Tween 20 / PBS) containing an anti-B220 antibody (Santacruz Biotech.) for 2 hours. After the slide was washed with PBS, the tissues fixed to the slide were incubated again with an avidin-conjugated secondary antibody and DAB solution.

[0206] As a result, various tumors were found i...

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Abstract

The present invention relates to novel uses of AIM3 acting as a tumor suppressor, and more particularly to methods for using an AIM3 protein or a nucleic acid encoding the protein to activate ATM or ATR and to treat ATM- or ATR-mediated diseases. The AIM3 protein according to the present invention interacts directly with ATM / ATR so as to activate ATM / ATR and proteins regulated by ATM / ATR. Also, the AIM3 protein upregulates tumor suppressor gene p53 and its target genes so as to not only inhibit the proliferation of cells but also to induce apoptosis.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel tumor suppressor, and particularly to a novel tumor suppressor that activates ATM or ATR. BACKGROUND ART [0002] Cells have a variety of fail-safe mechanisms, one of which is to arrest the cell division of damaged chromosomal DNA and to repair the damage, thus preventing mutations from settling. When chromosomal DNA damaged by UV and the like is continued to undergo cell division in a condition where the damage is not repaired, the damaged chromosomal DNA will be replicated so as to accumulate mutations. This leads to an increase in the incidence of cancer cells. Accordingly, when DNA is damaged, cells operate a process of repairing the damage and an intracellular feedback mechanism of arresting the cell division until the repair of DNA damage is over, followed by inhibiting the development of cancers. Such a feedback mechanism is mediated by checkpoints in each cycle of cell division. The overall function of these check...

Claims

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Application Information

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IPC IPC(8): A61K48/00C12Q1/68C07H21/04C12N9/22A61K38/00C07K14/47G01N33/574G01N33/68
CPCA01K2217/054A61K38/1709A61K38/53A61K48/00C07K14/47G01N2800/205C12N9/93G01N33/574G01N33/6893G01N2333/4703G01N2500/04C07K14/4702A61P13/08A61P13/10A61P17/06A61P35/00A61P35/02A61P43/00
Inventor KIM, SUNGHOON
Owner SCHWARZ HERBERT
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