Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response.
Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response.
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DOI：
10.1371/journal.pone.0004152
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Kenmochi N
中科院分区：
文献类型：
--
作者：
Chakraborty A;Uechi T;Higa S;Torihara H;Kenmochi N
核糖体负责所有生物体中的蛋白质合成，核糖体蛋白 (RP) 在功能核糖体的形成中发挥重要作用。 L11 最近被证明可以通过与 MDM2 直接结合来调节 p53 活性，并消除 MDM2 诱导的 p53 响应核糖体应激的降解。然而，这些研究是在细胞系中进行的，L11 的这种肿瘤抑制功能的重要性尚未在动物模型中探索。为了研究 L11 缺失的影响及其与 p53 活性的生理相关性，我们敲低了斑马鱼中的 rpl11 基因并分析了 p53 反应。与基于细胞系的结果相反，我们的数据表明模式生物中的 L11 缺陷会激活 p53 途径。 L11 缺陷胚胎（变形体）主要在大脑中表现出发育异常，导致胚胎在受精后 6-7 天内死亡。在变形体的头部区域观察到广泛的细胞凋亡，因此将形态缺陷与明显的细胞死亡相关联。在变形体中观察到涉及大脑神经模式的基因总丰度减少，表明神经祖细胞减少。在 morphant 中观察到参与 p53 途径的基因上调。同时敲除 p53 基因可挽救 morphant 的发育缺陷和细胞凋亡。这些结果表明，由于 L11 缺失导致的核糖体功能障碍会激活 p53 依赖性检查点反应，以防止胚胎发育不当。
Ribosome is responsible for protein synthesis in all organisms and ribosomal proteins (RPs) play important roles in the formation of a functional ribosome. L11 was recently shown to regulate p53 activity through a direct binding with MDM2 and abrogating the MDM2-induced p53 degradation in response to ribosomal stress. However, the studies were performed in cell lines and the significance of this tumor suppressor function of L11 has yet to be explored in animal models. To investigate the effects of the deletion of L11 and its physiological relevance to p53 activity, we knocked down the rpl11 gene in zebrafish and analyzed the p53 response. Contrary to the cell line-based results, our data indicate that an L11 deficiency in a model organism activates the p53 pathway. The L11-deficient embryos (morphants) displayed developmental abnormalities primarily in the brain, leading to embryonic lethality within 6–7 days post fertilization. Extensive apoptosis was observed in the head region of the morphants, thus correlating the morphological defects with apparent cell death. A decrease in total abundance of genes involved in neural patterning of the brain was observed in the morphants, suggesting a reduction in neural progenitor cells. Upregulation of the genes involved in the p53 pathway were observed in the morphants. Simultaneous knockdown of the p53 gene rescued the developmental defects and apoptosis in the morphants. These results suggest that ribosomal dysfunction due to the loss of L11 activates a p53-dependent checkpoint response to prevent improper embryonic development.
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影响因子：
9.8
作者：
Gazda, Hanna T.;Grabowska, Agnieszka;Sieff, Colin A.
通讯作者：
Sieff, Colin A.
影响因子：
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作者：
MARECHAL, V;ELENBAAS, B;LEVINE, AJ
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影响因子：
64.8
作者：
Ebert, Benjamin L.;Pretz, Jennifer;Bosco, Jocelyn;Chang, Cindy Y.;Tamayo, Pablo;Galili, Naomi;Raza, Azra;Root, David E.;Attar, Eyal;Ellis, Steven R.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
3.5
作者：
Miyoshi, K;Shirai, C;Mizuta, K
通讯作者：
Mizuta, K
DOI：
10.1073/pnas.0805036105
发表时间：
2008-07-29
影响因子：
11.1
作者：
MacInnes, Alyson W.;Amsterdam, Adam;Lees, Jacqueline A.
通讯作者：
Lees, Jacqueline A.