Dissecting the pathways that destabilize mutant p53 The proteasome or autophagy?
Dissecting the pathways that destabilize mutant p53 The proteasome or autophagy?
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DOI：
10.4161/cc.24128
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发表时间：
2013-04-01
期刊：
影响因子：
4.3
通讯作者：
Avantaggiati, Maria Laura
中科院分区：
文献类型：
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作者：
Choudhury, Sujata;Kolukula, Vamsi K.;Avantaggiati, Maria Laura
p53 突变形式的一个基本特征在于它们在肿瘤中高水平积累。至少在获得致癌活性的新形 p53 突变的情况下，稳定是肿瘤进展的驱动力。有充分证据表明，与野生型 p53 相比，p53 突变体能够抵抗蛋白酶体依赖性降解，但影响突变体 p53 稳定性的途径的确切身份仍然存在争议。我们最近发现，巨自噬（自噬）为葡萄糖限制期间 p53 突变体的降解提供了一条途径。在这里，我们进一步表明，在基础生长条件下，用化学抑制剂抑制自噬或通过下调必需自噬基因 ATG1/Ulk1、Beclin-1 或 ATG5 来抑制自噬，可导致 p53 突变体稳定。相反，Beclin-1 或 ATG1/Ulk1 的过度表达会导致 p53 突变体缺失。此外，我们发现在许多细胞系中，长期抑制蛋白酶体并不能稳定突变型 p53，而是会导致其自噬介导的降解。因此，我们得出结论，自噬是调节几种p53突变体稳定性的关键机制。我们讨论了这种新发现的降解途径中涉及的合理机制，以及自噬在突变 p53 驱动的肿瘤进化过程中可能发挥的作用。
One fundamental feature of mutant forms of p53 consists in their accumulation at high levels in tumors. At least in the case of neomorphic p53 mutations, which acquire oncogenic activity, stabilization is a driving force for tumor progression. It is well documented that p53 mutants are resistant to proteasome-dependent degradation compared with wild-type p53, but the exact identity of the pathways that affect mutant p53 stability is still debated. We have recently shown that macroautophagy (autophagy) provides a route for p53 mutant degradation during restriction of glucose. Here we further show that in basal conditions of growth, inhibition of autophagy with chemical inhibitors or by downregulation of the essential autophagic genes ATG1/Ulk1, Beclin-1 or ATG5, results in p53 mutant stabilization. Conversely, overexpression of Beclin-1 or ATG1/Ulk1 leads to p53 mutant depletion. Furthermore, we found that in many cell lines, prolonged inhibition of the proteasome does not stabilize mutant p53 but leads to its autophagic-mediated degradation. Therefore, we conclude that autophagy is a key mechanism for regulating the stability of several p53 mutants. We discuss plausible mechanisms involved in this newly identified degradation pathway as well as the possible role played by autophagy during tumor evolution driven by mutant p53.