INTERACTION BETWEEN A CELLULAR PROTEIN THAT BINDS TO THE C-TERMINAL REGION OF ADENOVIRUS E1A (CTBP) AND A NOVEL CELLULAR PROTEIN IS DISRUPTED BY E1A THROUGH A CONSERVED PLDLS MOTIF

Adenovirus E1A proteins immortalize primary animal cells and cooperate with several other oncogenes in oncogenic transformation. These activ ities are primarily determined by the N-terminal half (exon 1) of Elk Although the C-terminal half (exon 2) is also essential for some of th ese activities, it is dispensable for cooperative transformation with the activated T24 ras oncogene. Exon 2 negatively modulates in vitro c ooperative transformation with T24 ras as well as the tumorigenic and metastatic potentials of transformed cells. A short C-terminal sequenc e of ELA governs the oncogenesis-restraining activity of exon 2. This region of E1A binds with a cellular phosphoprotein, CtBP, through a 5- amino acid motif, PLDLS, conserved among the E1A proteins of human ade noviruses. To understand the mechanism by which interaction between E1 A and CtBP results in tumorigenesis-restraining activity, we searched for cellular proteins that complex with CtBP. Here, we report the clon ing and characterization of a 125-kDa protein, CtIP, that binds with C tBP through the PLDLS moth, E1A exon 2 peptides that contain the PLDLS moth disrupt the CtBP-CtIP complex. Our results suggest that the tumo rigenesis-restraining activity of E1A exon 2 may be related to the dis ruption of the CtBP-CtIP complex through the PLDLS moth.