Interaction of p53 with 14-3-3

摘要

The p53 tumor suppressor protein is a sequence-specific DNA binding transcription factor that induces cell cycle arrest or apoptosis in response to DNA damage. We had previously demonstrated that ionizing radiation (IR) leads to association of p53 with 14-3-3 in breast cancer cells and hypothesized that this association activates the tumor suppressor function of p53. To test this hypothesis, we had proposed to determine whether the interaction of p53 with 14- 3-3 affects: 1. the sequence-specific DNA binding activity of p53 (months 1-12); 2. the cell cycle arrest and/or apoptotic functions of p53 (months 13-24); and 3. p53 intracellular localization and half-life (months 25-36). During the three years of funding we showed that the interaction of p53 with 14-3-3 proteins does not affect p53 sequence- specific DNA binding activity in vivo (Task 1); that the interaction of p53 with 14-3-3 is critical for the ability of p53 to induce cell cycle arrest and that 14-3-3 proteins affect p53 function by regulating the transcriptional activity of p53 (Task 2); and that the interaction of p53 with 14-3-3 proteins does not affect p53 intracellular localization or half-life (Task 3). Overall, the results support the initial hypothesis that the interaction of p53 with 14-3-3 activates the tumor suppressor function of p53, although the mechanism turns out to be different than what we had expected. The 14-3-3 proteins affect the transcriptional activity of p53, rather than its DNA binding activity.