Novel use of aim 3 acting as a tumor suppressor

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.

1 . A method for activating one selected from ATM, ATR and proteins regulated by ATM or ATR, in the cell, tissue or individual, comprising administering to the cell, tissue or individual an effective amount of one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 (ARS-interacting multifunctional protein 3) having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         2 . The method of  claim 1 , wherein the activation of ATM or ATR is mediated by the binding of AIM3.  
     
     
         3 . The method of  claim 1 , wherein the proteins regulated by ATM or ATR are selected from the group consisting of H2AX, p53, chk2, chk1, BRC AI, c-Abl, PHAS-1, RPA, RAD9, MDM2, MRE11, Rad17, WRN, PTS, CtIP, eIF-4E binding protein 1, LKB1, FANCD2, SMCl, Rad17, Nibrin, NBS, p95, Pin2/TRF1, DNA 5B, BRC A2 and phosphatidylinositol 3-kinase.  
     
     
         4 . The method of  claim 1 , wherein the activation of ATM, ATR and proteins regulated by ATM or ATR is related with DNA repair, cell cycle regulation and/or apoptosis.  
     
     
         5 . A method for inducing the expression of p53 or its target genes in the cell, tissue or individual, comprising administering to the cell, tissue or individual an effective amount of one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 (ARS-interacting multifunctional protein 3) having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         6 . The method of  claim 5 , wherein the target genes of p53 are selected from the group consisting of p21, PUMA, GADD45, 14-3-3 sigma, WIPI, mdm-2, EGFR, PCNA, Cyclin D1, Cyclin G, TGFA, BAX, BAK, FAS1, Fas/APO1, FASL, IGF-BP3, PAG608, DR5/KILLER, GML, p53AIP1, p53R2, P2XM, TSP-1, BAL1, CSR, PIG3, Apaf-1, p53RDL1, Staf50, CD200 and Snk/PIk2.  
     
     
         7 . A method for inhibiting the proliferation of tumor cells, comprising administering to the cell, tissue or individual an effective amount of one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 (ARS-interacting multifunctional protein 3) having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         8 . A method for stimulating apoptosis in the cell, tissue or body, comprising administering to the cell, tissue or individual an effective amount of one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 (ARS-interacting multifunctional protein 3) having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         9 . A method for treating or preventing ATM- or ATR-mediated diseases, comprising administering to a subject in need thereof an effective amount of one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 (ARS-interacting multifunctional protein 3) having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         10 . The method of  claim 9 , wherein the diseases are cancers or psoriasis.  
     
     
         11 . The method of  claim 10 , wherein the cancers include 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 neat 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, uterine cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or urethra cancer, kidney cell carcinoma, kidney pelvis carcinoma, CNS tumor, primary CNS lymphoma, spinal tumor, brain stem glioma, and pituitary adenoma, and combinations of one or more thereof.  
     
     
         12 . A method for screening a substance having the effect of treating and/or preventing ATM- or ATR-mediated diseases, comprising the steps of: 
 (a) culturing AIM3 (ARS-interacting multifunctional protein 3) or a recombinant cell expressing the protein, together with a candidate substance; and    (b) determining the effect of the candidate substance on an increase in the activity of AIM3 or intracellular level thereof.    
     
     
         13 . The method of  claim 12 , wherein the ATM- or ATR-mediated diseases are cancers or psoriasis.  
     
     
         14 . A method for identifying a subject having the risk of ATM- or ATR-mediated diseases, comprising the steps of: 
 (a) measuring the expression level of AIM3 (ARS-interacting multifunctional protein 3) in tissue sampled from a subject; and    (b) comparing the AIM3 level in the tissue with a normal AIM3 level.    
     
     
         15 . The method of  claim 14 , wherein the ATM- or ATR-mediated diseases are cancers or psoriasis.  
     
     
         16 . A kit for the diagnosis of ATM- or ATR-mediated diseases, comprising one selected from a AIM3 protein-encoding nucleic acid, its fragment, a peptide encoded by the nucleic acid or its fragment, and an antibody to the peptide.  
     
     
         17 . The method of  claim 16 , wherein the ATM- or ATR-mediated diseases are cancers or psoriasis.  
     
     
         18 . A pharmaceutical composition for activating one selected from ATM, ATR and proteins regulated by ATM or ATR, in the cell, tissue or individual, comprising, as an active ingredient, one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         19 . A pharmaceutical composition for inducing the expression of p53 or its target genes in the cell, tissue or individual, comprising, as an active ingredient, one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         20 . A pharmaceutical composition for inhibiting the proliferation of tumor cells, comprising, as an active ingredient, one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         21 . A pharmaceutical composition for stimulating apoptosis in the cell, tissue or individual, comprising, as an active ingredient, one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         22 . A pharmaceutical composition for treating or preventing ATM- or ATR-mediated diseases, comprising, as an active ingredient, one selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1;    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with the polypeptide (a); and    (c) an isolated nucleic acid encoding the polypeptide (a) or (b).    
     
     
         23 . An isolated polypeptide for use as an active therapeutic substance, being selected from the group consisting of the following: 
 (a) an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1; and    (b) an isolated polypeptide having an amino acid sequence homology of at least 70% with said polypeptide.    
     
     
         24 . An isolated nucleic acid for use as an active therapeutic substance, encoding an isolated polypeptide of AIM3 having an amino acid sequence shown in SEQ ID NO: 1 or an isolated polypeptide having a sequence homology of at least 70% with said polypeptide.