Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate.
Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate.
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DOI：
10.1083/jcb.200512059
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发表时间：
2006-05-22
期刊：
影响因子：
--
通讯作者：
Avantaggiati ML
中科院分区：
文献类型：
--
作者：
Knights CD;Catania J;Di Giovanni S;Muratoglu S;Perez R;Swartzbeck A;Quong AA;Zhang X;Beerman T;Pestell RG;Avantaggiati ML
p53基因产物的活性受到大量翻译后修饰的调节。一个悬而未决的问题是这样的翻译后变化是否冗余或相互依赖的行为。我们发现，特定的乙酰化和磷酸化的p53残基之间的功能干扰影响细胞的命运。赖氨酸320（K320）的乙酰化可防止p53的NH 2-末端区域中关键丝氨酸的磷酸化;仅允许含有高亲和力p53结合位点的基因（如p21/WAF）活化;并促进DNA损伤后的细胞存活。相反，K373的乙酰化导致p53 NH 2-末端残基的过度磷酸化，并增强与p53具有低DNA结合亲和力的启动子的相互作用，例如那些包含在促凋亡基因中的启动子，导致细胞死亡。此外，这两个赖氨酸簇的乙酰化差异调节p53与辅激活因子和辅阻遏因子的相互作用，并产生不同的基因表达谱。通过与“组蛋白密码”假设类比，我们提出p53的多种生物活性是由不同的“p53盒”精心安排和破译的，每个盒都包含翻译后修饰和蛋白质-蛋白质相互作用的组合模式。
The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH2-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH2-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the “histone code” hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different “p53 cassettes,” each containing combination patterns of posttranslational modifications and protein–protein interactions.
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