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首页> 外文期刊>Molecular and Cellular Biology >Stimulation of p53 DNA Binding by c-Abl Requires the p53 C Terminus and Tetramerization
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Stimulation of p53 DNA Binding by c-Abl Requires the p53 C Terminus and Tetramerization

机译：c-Abl刺激p53 DNA结合需要p53 C末端和四聚体作用

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The carboxyl terminus of p53 is a target of a variety of signals for regulation of p53 DNA binding. Growth suppressor c-Abl interacts with p53 in response to DNA damage and overexpression of c-Abl leads to G1 growth arrest in a p53-dependent manner. Here, we show that c-Abl binds directly to the carboxyl-terminal regulatory domain of p53 and that this interaction requires tetramerization of p53. Importantly, we demonstrate that c-Abl stimulates the DNA-binding activity of wild-type p53 but not of a carboxyl-terminally truncated p53 (p53Δ363C). A deletion mutant of c-Abl that does not bind to p53 is also incapable of activating p53 DNA binding. These data suggest that the binding to the p53 carboxyl terminus is necessary for c-Abl stimulation. To investigate the mechanism for this activation, we have also shown that c-Abl stabilizes the p53-DNA complex. These results led us to hypothesize that the interaction of c-Abl with the C terminus of p53 may stabilize the p53 tetrameric conformation, resulting in a more stable p53-DNA complex. Interestingly, the stimulation of p53 DNA-binding by c-Abl does not require its tyrosine kinase activity, indicating a kinase-independent function for c-Abl. Together, these results suggest a detailed mechanism by which c-Abl activates p53 DNA-binding via the carboxyl-terminal regulatory domain and tetramerization.
机译：p53的羧基末端是调节p53 DNA结合的各种信号的靶标。生长抑制剂c-Abl与p53相互作用以响应DNA损伤，而c​​-Abl的过表达导致p <53>依赖于G 1 的生长停滞。在这里，我们显示c-Abl直接与p53的羧基末端调节域结合，并且这种相互作用需要p53的四聚化。重要的是，我们证明c-Abl刺激野生型p53的DNA结合活性，但不刺激羧基末端截短的p53（p53Δ363C）的DNA结合活性。不结合p53的c-Abl缺失突变体也不能激活p53 DNA结合。这些数据表明，结合到p53羧基末端对于c-Abl刺激是必要的。为了研究这种激活的机制，我们还显示了c-Abl可以稳定p53-DNA复合物。这些结果使我们假设c-Abl与p53的C末端的相互作用可以稳定p53的四聚体构象，从而产生更稳定的p53-DNA复合物。有趣的是，c-Abl刺激p53 DNA结合不需要其酪氨酸激酶活性，这表明c-Abl具有独立于激酶的功能。总之，这些结果表明了c-Abl通过羧基末端调节域和四聚化激活p53 DNA结合的详细机制。

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