Inhibitors of the JNK signal transduction pathway and methods of use

Abstract

JNK-interacting protein 1 (JIP-1), an inhibitor of the JNK1 protein, and methods of treating a pathological condition or of preventing the occurrence of a pathological condition in a patient by the administration of a therapeutically effective amount of JIP-1 polypeptides, peptides, peptide mimetics, or nucleic acids are described.

What is claimed is:  
     
         1 . A substantially pure JNK-interacting protein 1 (JIP-1) polypeptide or a biologically active fragment thereof.  
     
     
         2 . The polypeptide of  claim 1 , wherein said polypeptide is modified by attachment of a hydrophobic moiety, to facilitate uptake of said polypeptide by cells.  
     
     
         3 . The polypeptide of  claim 2 , wherein said polypeptide is modified by attachment of a peptide that facilitates uptake of said polypeptide by cells.  
     
     
         4 . The polypeptide of  claim 1 , wherein said polypeptide comprises an amino acid sequence corresponding to the JNK-binding domain (JBD; SEQ ID NO:4) of wild type JIP-1.  
     
     
         5 . The polypeptide of  claim 1 , said polypeptide comprising an amino acid sequence substantially identical to SEQ ID NO:1.  
     
     
         6 . The polypeptide of  claim 1 , said polypeptide comprising an amino acid sequence substantially identical to a sequence selected from the group consisting SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:13; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:22; SEQ ID NO:23; and SEQ ID NO:24.  
     
     
         7 . The polypeptide of  claim 1 , wherein said polypeptide is of mammalian origin.  
     
     
         8 . The polypeptide of  claim 1 , wherein said polypeptide is of human origin.  
     
     
         9 . Isolated nucleic acid comprising a sequence encoding the polypeptide of  claim 1 , or its complement.  
     
     
         10 . The nucleic acid of  claim 9 , wherein said nucleic acid comprises a sequence encoding a JNK-binding domain.  
     
     
         11 . The nucleic acid of  claim 9 , said nucleic acid comprising a nucleotide sequence substantially identical to SEQ ID NO:12 or its complement.  
     
     
         12 . The nucleic acid of  claim 9 , said nucleic acid encoding the amino acid sequence of SEQ ID NO:1.  
     
     
         13 . A genetically engineered host cell comprising the nucleic acid of  claim 9 .  
     
     
         14 . An expression vector comprising the nucleic acid of  claim 9 , operably linked to a nucleotide sequence regulatory element that controls expression of the nucleotide sequence in a host cell.  
     
     
         15 . The nucleic acid of  claim 9 , wherein said nucleic acid is of mammalian origin.  
     
     
         16 . The nucleic acid of  claim 9 , wherein said nucleic acid is of human origin.  
     
     
         17 . A method of treating a patient having a pathological condition associated with abnormal expression or activity of JNK, or at risk of developing a pathological condition associated with abnormal activity or expression of JNK, said method comprising administering to the patient a therapeutically effective amount of a JIP-1 nucleic acid.  
     
     
         18 . The method of  claim 17 , wherein said pathological condition is a neurodegenerative disease.  
     
     
         19 . The method of  claim 17 , wherein said neurodegenerative disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.  
     
     
         20 . The method of  claim 17 , wherein said pathological condition is a blood clot.  
     
     
         21 . The method of  claim 17 , wherein said condition is stroke.  
     
     
         22 . The method of  claim 17 , wherein said pathological condition is malignancy.  
     
     
         23 . The method of  claim 17 , wherein said pathological condition is leukemia.  
     
     
         24 . The method of  claim 23 , wherein said leukemia is chronic myelogenous leukemia.  
     
     
         25 . The method of  claim 17 , wherein said pathological condition is an autoimmune disease.  
     
     
         26 . The method of  claim 17 , wherein said pathological condition is inflammation.  
     
     
         27 . A method of treating a patient having a pathological condition associated with abnormal expression or activity of JNK, or at risk of developing a pathological condition associated with abnormal activity or expression of JNK, said method comprising administering to the patient a therapeutically effective amount of a JIP-1 polypeptide.