Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics
Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics
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DOI：
10.1073/pnas.132275599
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发表时间：
2002-08-06
影响因子：
11.1
通讯作者：
Fojo, T
中科院分区：
文献类型：
--
作者：
Giannakakou, P;Nakano, M;Fojo, T
肿瘤抑制蛋白p53定位于微管（MT），并且响应于DNA损伤，通过MT负末端定向运动蛋白动力蛋白转运到细胞核。动力蛋白还负责MT介导的2型腺病毒（Ad 2）的核靶向。在这里，我们表明，治疗与低浓度的MT靶向化合物（MTCs），不破坏MT网络，但已知抑制MT动力学增强p53核积累，和激活的p53下游靶基因。p53核积累需要MTCs与MTs的结合，并增强了p53上调的凋亡调节因子（p53-up-regulated modulator of apoptosis，MAPA）mRNA的诱导，以及用DNA损伤药物阿霉素攻击细胞时的凋亡。低浓度的MTCs增强了荧光Ad 2向细胞核的移动速率，并增加了Ad 2的核靶向效率。我们认为，低浓度MTCs对MT动力学的抑制增强了MT依赖的向MT负端的运输，并促进了核靶向。
The tumor suppressor protein p53 localizes to microtubules (MT) and, in response to DNA damage, is transported to the nucleus via the MT minus-end-directed motor protein dynein. Dynein is also responsible for MT-mediated nuclear targeting of adenovirus type 2 (Ad2). Here we show that treatment with low concentrations of MT-targeting compounds (MTCs) that do not disrupt the MT network but are known to suppress MT dynamics enhanced p53 nuclear accumulation, and the activation of the p53-downstream target genes. p53 nuclear accumulation required binding of MTCs to MTs and enhanced the induction of p53-up-regulated modulator of apoptosis (PUMA) mRNA and apoptosis on challenging cells with the DNA-damaging drug adriamycin. Low concentrations of MTCs enhanced the rate of movement of fluorescent Ad2 to the nucleus and increased the nuclear targeting efficiency of Ad2. We propose that suppression of MT dynamics by low concentrations of MTCs enhances MT-dependent trafficking toward the minus ends of MTs and facilitates nuclear targeting.