PLoS ONE：Mdm2-p53通路新发现

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<div>近日，来自美国北卡罗来纳大学教堂山分校的研究人员发现，Mdm2内RING结构域的突变使其丧失了E3泛素连接酶活性，却增强了p53的转录活性及p53-p300之间的相互作用。相关研究成果于5月29日发表在<em>PLoS ONE</em>上。</div>
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p53基因是一种抑癌基因，是细胞生长周期中的负调节因子，与细胞周期的调控、DNA修复、细胞分化、细胞凋亡等重要的生物学功能息息相关。p53主要被E3泛素连接酶Mdm2所调节，Mdm2泛素化p53，然后由蛋白酶体所降解。Mdm2除了具有泛素连接酶的作用外，现在已经广泛的认为它还能够抑制p53的转录活性，这主要是通过它结合并掩盖p53的反式激活结构域所致。

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以往的研究认为，Mdm2抑制p53活性的能力与Mdm2的泛素连接酶活性无关，仅仅是通过Mdm2与之结合所致。但是2007年的一项研究否认了这个观点，研究人员在小鼠细胞内Mdm2的RING结构域敲入了一个半胱氨酸到丙氨酸的点突变(C462A)。因此，老鼠的胚胎成纤维细胞具有这种突变。后续研究发现，这种突变的Mdm2失去了E3泛素连接酶活性，而且它仍能够结合到p53，但是它却丧失了抑制p53的作用。

在这项研究里，研究人员Hilary V. Clegg等人利用<em>Mdm2^{<span style="font-size: x-small;">C462A</span>}</em> 小鼠模型，进一步研究了Mdm2的RING结构域对p53的影响。研究发现，在体内Mdm2^{<span style="font-size: x-small;">C462A</span>}蛋白不仅不会抑制p53，对比于完全缺乏Mdm2，Mdm2^{<span style="font-size: x-small;">C462A</span>}却增强了p53对其靶基因<em>p21/CDKN1A、MDM2、BAX、NOXA</em>及<em>14-3-3σ</em>的转录活性。

除此以外，他们还发现， Mdm2^{<span style="font-size: x-small;">C462A</span>} 促进了p53与乙酰基转移酶CBP/p300之间的相互作用，而且 Mdm2^{<span style="font-size: x-small;">C462A</span>} 不能与它的同源物及Mdmx异聚化。这表明Mdm2抑制p300-p53之间的相互作用，Mdm2与Mdmx之间的相互作用都需要完整地RING结构域。

为此，Hilary V. Clegg表示，该研究能够帮助我们更好的理解Mdm2-p53通路复杂的调节机制，并对靶向Mdm2的化疗药物的开发具有重要的影响。 
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<a title="" href="http://dx.doi.org/10.1371/journal.pone.0038212" target="_blank">doi: 10.1371/journal.pone.0038212</a>
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<br/><strong>Mdm2 RING Mutation Enhances p53 Transcriptional Activity and p53-p300 Interaction </strong><br/>


Hilary V. Clegg, Yoko Itahana, Koji Itahana, Sundhar Ramalingam, Yanping Zhang.

The p53 transcription factor and tumor suppressor is regulated primarily by the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 to target it for proteasomal degradation. Aside from its ubiquitin ligase function, Mdm2 has been believed to be capable of suppressing p53's transcriptional activity by binding with and masking the transactivation domain of p53.The ability of Mdm2 to restrain p53 activity by binding alone, without ubiquitination, was challenged by a 2007 study using a knockin mouse harboring a single cysteine-to-alanine point mutation (C462A) in Mdm2's RING domain. Mouse embryonic fibroblasts with this mutation, which abrogates Mdm2's E3 ubiquitin ligase activity without affecting its ability to bind with p53, were unable to suppress p53 activity.In this study, we utilized the Mdm2C462A mouse model to characterize in further detail the role of Mdm2's RING domain in the control of p53. Here, we show in vivo that the Mdm2C462A protein not only fails to suppress p53, but compared to the complete absence of Mdm2, Mdm2C462A actually enhances p53 transcriptional activity toward p53 target genes p21/CDKN1A, MDM2, BAX, NOXA, and 14-3-3σ.In addition, we found that Mdm2C462A facilitates the interaction between p53 and the acetyltransferase CBP/p300, and it fails to heterodimerize with its homolog and sister regulator of p53, Mdmx, suggesting that a fully intact RING domain is required for Mdm2's inhibition of the p300-p53 interaction and for its interaction with Mdmx.These findings help us to better understand the complex regulation of the Mdm2-p53 pathway and have important implications for chemotherapeutic agents targeting Mdm2, as they suggest that inhibition of Mdm2's E3 ubiquitin ligase activity may be sufficient for increasing p53 activity in vivo, without the need to block Mdm2-p53 binding.
<div> <br/>来源：生物谷</div>
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