Signaling to p53: breaking the posttranslational modification code.
Signaling to p53: breaking the posttranslational modification code.
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发表时间：
2000-04
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通讯作者：
E. Appella;Anderson Cw
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作者：
E. Appella;Anderson Cw
在非应激细胞中，肿瘤抑制蛋白p53（一种四聚体转录因子）以潜伏状态存在，并通过靶向降解维持在低水平。多种细胞应激，包括DNA损伤、缺氧、核苷酸耗竭、病毒感染和丝氨酸激活的信号通路，其瞬时稳定p53蛋白，使其在细胞核中积累，并将其激活为转录因子。激活导致细胞周期的G1/S或G2/M转换时的生长停滞或细胞凋亡。稳定和激活发生的分子机制尚不完全清楚，但越来越多的证据表明，多个翻译后修饰通过几个潜在的相互作用，但不同的途径介导这些事件的作用。大约100个氨基酸的N-末端和大约90个氨基酸的C-末端结构域都被磷酸化和乙酰化高度修饰，而对中心序列特异性DNA结合结构域的修饰尚未报道。现在已知反式激活结构域的前46个残基中的7个丝氨酸和1个苏氨酸以及羧基末端结构域中的4至5个丝氨酸被磷酸化，并且羧基末端结构域（人p53）中的Lys 320和Lys 382可以被乙酰化。几个实验室已经开发出了仅在p53在特定位点被修饰时才识别p53的抗体，并且对这些抗体的研究表明，当细胞暴露于DNA损伤剂时，大多数已知的翻译后修饰被诱导。它们是Ser 378和Ser 376，据报道Ser 378是组成性磷酸化的，Ser 376是响应于DNA损伤而去磷酸化的。这些最近的结果，加上生物化学和遗传学的研究，表明，几个氨基末端磷酸化可以是重要的稳定p53在响应DNA损伤和指导乙酰化在C-末端位点。DNA损伤诱导的C-末端修饰通过诱导蛋白质的构象变化或通过抑制C-末端的非序列特异性DNA结合来抑制该结构域负调节序列特异性DNA结合的能力。C-末端修饰也调节p53的寡聚化状态，并且可以调节核输入/输出。与p53相互作用的其他成分对DNA损伤的反应也可能是重要的。在大多数情况下，特定修饰的明确作用，单个修饰之间的相互作用以及负责每个修饰的酶仍有待确定。尽管如此，该领域似乎准备在理解调节p53功能的分子机制方面取得重大进展。
In unstressed cells, the tumor suppressor protein p53, a tetrameric transcription factor, is present in a latent state and is maintained at low levels through targeted degradation. A variety of cellular stresses including DNA damage, hypoxia, nucleotide depletion, viral infection, and cytokine-activated signaling pathways that transiently stabilize the p53 protein, cause it to accumulate in the nucleus, and activate it as a transcription factor. Activation leads either to growth arrest at the G1/S or G2/M transitions of the cell cycle or to apoptosis. The molecular mechanisms by which stabilization and activation occur are incompletely understood, but accumulating evidence points to roles for multiple posttranslational modifications in mediating these events through several potentially interacting but distinct pathways. Both the approximately 100 amino acid N-terminal and approximately 90 amino acid C-terminal domains are highly modified by phosphorylation and acetylation, whereas modifications to the central sequence-specific DNA binding domain have not been reported. Seven serines and one threonine in the first 46 residues of the transactivation domain and four to five serines in the carboxyl-terminal domain are now known to be phosphorylated, and Lys320 and Lys382 in the carboxyl-terminal domain (human p53) can be acetylated. Antibodies that recognize p53 only when it has been modified at specific sites have been developed by several laboratories, and studies with these have shown that most of the known posttranslational modifications are induced when cells are exposed to DNA-damaging agents. Exceptions are Ser378, which is reported to be constitutively phosphorylated, and Ser376, which is dephosphorylated in response to DNA damage. These recent results, coupled with biochemical and genetic studies, suggest that several amino-terminal phosphorylations can be important in stabilizing p53 in response to DNA damage and in directing acetylation at C-terminal sites. DNA damage-induced modifications to the C-terminus inhibit the ability of this domain to negatively regulate sequence-specific DNA binding either by inducing a conformational change in the protein or by inhibiting non-sequence-specific DNA binding by the C-terminus. C-terminal modifications also modulate the oligomerization state of p53, and may modulate nuclear import/export. Modifications in response to DNA damage to other components that interact with p53 may also be important. In most cases, clear roles for specific modifications, interactions among individual modifications, and the enzymes responsible for each modification remain to be defined. Nevertheless, the field appears poised for major advances in the understanding of the molecular mechanisms that regulate p53 function.