Method of modulating and antiapoptotic and antiapoptotic pathways in cells

A method of reversing an oncogene-induced chemoresistance in transformed cell which comprises decreasing the amount of eIF4F pre-initiation complex, thereby decreasing the translation of mRNAs implicated in oncogene-induced chemoresistance.

A method of selecting a compound that modulates direct binding of 4E-BP1 with eIF4E comprising the steps of:

• (a) incubating a candidate compound with a first polypeptide comprising a 4E-BP1 interaction domain and a second polypeptide comprising an eIF4E interaction domain under conditions wherein said 4E-BP1 interaction domain binds to said eIF4E interaction domain in the absence of said candidate compound;
• and
• (b) determining the amount of a binding complex formed between said first polypeptide and said second polypeptide, wherein a potential modulating compound is selected when an amount of said binding complex formed in the presence of said candidate compound is measurably different than in the absence thereof.

A method of selecting a compound that increases or potentiates a pro-apoptotic function of 4E-BP1 in a cell in which apoptotic function is blocked or inhibited, comprising the steps of:

• a) incubating a candidate compound with a first polypeptide comprising a 4E-BP1 interaction domain and a second polypeptide comprising an eIF4E interaction domain and cap structure binding domain, under conditions wherein said 4E-BP1 interaction domain binds to said eIF4E interaction domain in the absence of said candidate compound;
• and
• b) determining the amount of a binding complex between said first polypeptide and said second polypeptide, using a cap affinity column to capture said second polypeptide through its cap structure binding site and associated binding partners, wherein a compound that potentiates or increases the pro-apoptotic function of 4E-BP1 is selected when an amount of said binding complex formed between said first and second polypeptide in the presence of said candidate compound is measurably different than in the absence thereof.

A method of immortalizing an oncogene-induced transformed cell which comprises increasing the amount of eIF4F pre-initiation complex, thereby increasing the translation of mRNAs implicated in the oncogene-induced anti-apoptotic pathway.

Use of an eIF4E sequestering agent, 4E-BP1 or an eIF4E binding portion thereof for treating high proliferative cells.

A method of treating cancer comprising a treatment of oncogene-induced cancer cells with a combination of chemotherapeutic agent and an agent which decreases the amount of active pre-initiation complex.