
<ArticleTitle>Inactivation of <prot>p21</prot> by <prot>E1A</prot> leads to the induction of apoptosis in DNA-damaged cells.</ArticleTitle>
<AbstractText>A major impediment to successful chemotherapy is the propensity for some tumor cells to undergo cell cycle arrest rather than apoptosis. It is well established, however, that the adenovirus <prot>E1A</prot> protein can sensitize these cells to the induction of apoptosis by anticancer agents. To further understand how <prot>E1A</prot> enhances chemosensitivity, we have made use of a human colon carcinoma cell line (HCT116) which typically undergoes cell cycle arrest in response to chemotherapeutic drugs. As seen by the analysis of <prot>E1A</prot> mutants, we show here that <prot>E1A</prot> can induce apoptosis in these cells by neutralizing the activities of the cyclin-dependent kinase inhibitor <prot>p21</prot>. <prot>E1A</prot>'s ability to interact with <prot>p21</prot> and thereby restore <prot>Cdk2</prot> activity in DNA-damaged cells correlates with the reversal of G(1) arrest, which in turn leads to apoptosis. Analysis of <prot>E1A</prot> mutants failing to bind <prot>p300</prot> (also called <prot>CBP</prot>) or <prot>Rb</prot> shows that they are almost identical to wild-type <prot>E1A</prot> in their ability to initially overcome a G(1) arrest in cells after DNA damage, while an <prot>E1A</prot> mutant failing to bind <prot>p21</prot> is not. However, over time, this mutant, which can still target <prot>Rb</prot>, is far more efficient in accumulating cells with a DNA content greater than 4N but is similar to wild-type <prot>E1A</prot> and the other <prot>E1A</prot> mutants in releasing cells from a p53-mediated G(2) block following chemotherapeutic treatment. Thus, we suggest that although <prot>E1A</prot> requires the binding of <prot>p21</prot> to create an optimum environment for apoptosis to occur in DNA-damaged cells, <prot>E1A</prot>'s involvement in other pathways may be contributing to this process as well. A model is proposed to explain the implications of these findings.</AbstractText>
