Compositions and methods for inhibiting tumor cells by inhibiting the transcription factor atf5

Abstract

The present invention relates to methods for treating and/or preventing tumors and/or promoting apoptosis in a neoplastic cell comprising contacting the neoplastic cell with an cell-penetrating dominant-negative ATF5 (“CP-d/n-ATF5”), wherein the CP-d/n-ATF5 is capable of inhibiting ATF5 function and/or activity.

1 . A method for treating and/or preventing tumors and/or promoting apoptosis in a neoplastic cell comprising contacting the neoplastic cell with an cell-penetrating dominant-negative ATF5, wherein the cell-penetrating dominant-negative ATF5 is capable of inhibiting ATF5 function and/or activity. 
     
     
         2 . The method of  claim 1 , wherein the neoplastic cell is selected from the group consisting of: breast, ovary, endometrium, gastric, colon, liver, pancreas, kidney, bladder, prostate, testis, skin, esophagus, tongue, mouth, parotid, larynx, pharynx, lymph node, lung, peripheral nervous system and brain. 
     
     
         3 . The method of  claim 2 , wherein the neoplastic brain cell is selected from the group consisting of glioblastoma, astrocytoma, glioma, medulloblastoma mesothelioma, and neuroblastoma, and the neoplastic brain cell is associated with a primary or a recurrent brain tumor. 
     
     
         4 . The method of  claim 1 , wherein the cell-penetrating dominant-negative ATF5 is administered orally, parenterally, and/or transdermally. 
     
     
         5 . A composition comprising a cell-penetrating dominant-negative ATF5, wherein the cell-penetrating dominant-negative ATF5 consists of a sequence selected from the group consisting of: 
       
         
           
                 
               
                     LEQENAE LEGECQGLEARNRELKERAES, 
                 
                     
                 
                     LEKEAEELEQENAE LEGECQGLEARNRE LKERAES, 
                 
                     
                 
                     LARENEELLEKEAEELEQENAE LEGECQGLEARNRELKERAES, 
                 
                     
                 
                     LEQRAEELARENEELLEKEAEELEQENAE LEGECQGLEARNRELKERAES, 
                 
                     
                 
                     LEQRAEELARENEELLEKEAEELEQENAE LEGECQGLEARNRELKERAESV, 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       where the underlined sequence is the dominant-negative sequence and the remainder of the sequence is the ATF5 leucine zipper, and the sequence is operably lined to a cell-penetrating sequence. 
     
     
         6 . A composition comprising a cell-penetrating dominant-negative ATF5, wherein the cell-penetrating dominant-negative ATF5 consists of a sequence selected from the group 
       
         
           
                 
               
                     LEQENAE LEGECQGLEARNRELRERAES, 
                 
                     
                 
                     LEKEAEELEQENAE LEGECQGLEARNRE LRERAES, 
                 
                     
                 
                     LARENEELLEKEAEELEQENAE LEGECQGLEARNRELRERAES, 
                 
                     
                 
                     LEQRAEELARENEELLEKEAEELEQENAE LEGECQGLEARNRELRERAES, 
                 
                     
                 
                     LEQRAEELARENEELLEKEAEELEQENAE LEGECQGLEARNRELRERAESV, 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       consisting of: 
       where the underlined sequence is the dominant-negative sequence and the remainder of the sequence is the ATF5 leucine zipper, and the sequence is operably lined to a cell-penetrating sequence. 
     
     
         7 . The composition of  claim 6 , wherein the cell-penetrating dominant-negative ATF5 comprises a sequence selected from the group consisting In certain embodiments, the cell-penetrating dominant-negative ATF5 comprises a sequence selected from the group consisting of: 
       
         
           
                 
               
                   (1) 
                 
                     MGSSHHHHHHSSGLVPRGSHM   RQIKIWFQNRRMKWKK   DYKDDDDK MAS 
                 
                     
                 
                   MTGGQQMGRDPD     
                 
                     
                 
                       LEGECQGLEARNRELRERAES V   , 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       where the underlined residues (MG-HM) are a 6×His-tag leader sequence, the bold residues (RQ-KK) are a Penetratin sequence, the italicized residues (DY-DK) are a Flag tag, the residues with no font modification (MA-PD) are spacer amino acids, the bold and italicized residues (LE-AE) are a d/n sequence, and the bold and underlined residues (LE-SV) are an ATF5 leucine zipper truncated after its first Valine; 
       
         
           
                 
               
                   (2) 
                 
                     MGSSHHHHHHSSGLVPRGSHMLE   YGRKKRRQRRR   YPYDVPDYA MASMTG 
                 
                     
                 
                   GQQMGRDPD       LEGECQGLE     
                 
                     
                 
                       ARNRELRERAESV   , 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       where the underlined residues (MG-LE) are a 6×His-tag leader sequence, the bold residues (YC-RR) are a TAT sequence, the italicized residues (YP-YA) are an HA tag, the residues with no font modification (MA-PD) are spacer amino acids, the bold and italicized residues (LE-AE) are a d/n sequence, and the bold and underlined residues (LE-SV) are an ATF5 leucine zipper truncated after its first Valine; 
       
         
           
                 
               
                   (3) 
                 
                   
                     MGSSHHHHHHSSGLVPRGSHM 
                     RQIKIWFQNRRMKWKK 
                     LEQRAEELAREN 
                   
                 
                   
                     E ELLEKEAEELEQENAE 
                     
                       LEGEC 
                       Q 
                       GLEARNRELKERAESV 
                     
                   
                 
             
                
                
                
               
            
           
         
       
       where the where the underlined residues (MG-HM) are a 6×His-tag leader sequence, the bold residues (RQ-KK) are a Penetratin sequence, the italicized residues (LE-AE) are a din sequence, and the bold and underlined residues (LE-SV) are an ATF5 leucine zipper truncated after its first Valine; and 
       
         
           
                 
               
                   (4) 
                 
                   
                     RQIKIWFQNRRMKWKK 
                     LEQRAEELARENEELLEKEAEELEQENAE 
                     
                       LEGE 
                     
                   
                 
                   
                     
                       CQ GLEARNRELKERAESV 
                     
                   
                 
             
                
                
                
               
            
           
         
       
       where the bold residues (RQ-KK) are a Penetratin sequence, the italicized residues (LE-AE) are a d/n sequence, and the bold and underlined residues (LE-SV) are an ATF5 leucine zipper truncated after its first Valine. 
     
     
         8 . A kit comprising a composition comprising a cell-penetrating dominant-negative ATF5 of any one of  claims 5 - 7 .