p53 upregulation is a frequent response to deficiency of cell-essential genes.
p53 upregulation is a frequent response to deficiency of cell-essential genes.
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DOI：
10.1371/journal.pone.0015938
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发表时间：
2010-12-31
期刊：
影响因子：
3.7
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Danilova N;Kumagai A;Lin J
p53 在预防受基因毒性因素损害的胚胎发育中的作用已得到广泛认可。然而，p53 是否在预防基因突变导致的出生缺陷方面发挥类似作用仍然是一个悬而未决的问题。对影响发育的突变进行基因筛查表明，只有一小部分发育致死突变会导致特定的表型，而大多数突变会导致类似的复发表型，其特征是神经元凋亡和发育迟缓。细胞必需基因的突变通常属于这一类。不同管家基因的突变导致相似的表型的观察结果表明，这种表型背后有一个共同的机制。对于一些突变体，p53 抑制被证明可以减弱表型。为了了解 p53 在这种表型中的参与程度，我们分析了来自不同类别细胞必需基因的斑马鱼突变体。已鉴定出数千种斑马鱼突变体；其中许多保存在库存中心并可供研究界使用。我们选择了在 DNA 复制、转录、端粒维持、核糖体生物合成、剪接、陪伴、内吞作用和细胞运输中发挥作用的基因突变体。我们发现突变体具有相似的表型，包括神经细胞凋亡、未能发育出源自神经嵴细胞的结构以及造血缺陷。所有突变体都具有 p53 上调以及一些 p53 依赖性和独立分子途径的类似变化。我们的结果表明，管家基因的突变通常会影响 p53 介导的表型。 p53 阻止具有此类基因缺陷的胚胎发育。 p53 介导的基因表达变化也可能导致许多人类先天畸形。
The role of p53 in the prevention of development of embryos damaged by genotoxic factors is well recognized. However, whether p53 plays an analogous role in preventing birth defects from genetic mutations remains an unanswered question. Genetic screens for mutations affecting development show that only a fraction of developmentally lethal mutations leads to specific phenotypes while the majority results in similar recurrent phenotypes characterized by neuronal apoptosis and developmental delay. Mutations in cell-essential genes typically fall into this group. The observation that mutations in diverse housekeeping genes lead to a similar phenotype suggests a common mechanism underlying this phenotype. For some mutants, p53 inhibition was shown to attenuate the phenotype. To find out how common p53 involvement is in this phenotype, we analyzed zebrafish mutants from various categories of cell essential genes. Several thousand zebrafish mutants have been identified; many of them are kept at stock centers and available for the research community. We selected mutants for genes functioning in DNA replication, transcription, telomere maintenance, ribosome biogenesis, splicing, chaperoning, endocytosis, and cellular transport. We found that mutants have similar phenotypes including neural apoptosis, failure to develop structures originated from the neural crest cells, and hematopoietic defects. All mutants share p53 upregulation and similar changes in several p53-dependent and independent molecular pathways. Our results suggest that mutations in housekeeping genes often canalize on the p53-mediated phenotype. p53 prevents the development of embryos with defects in such genes. p53-mediated changes in gene expression may also contribute to many human congenital malformations.
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影响因子：
6.5
作者：
Danilova N;Sakamoto KM;Lin S
通讯作者：
Lin S
影响因子：
64.5
作者：
Li, XL;Manley, JL
通讯作者：
Manley, JL
DOI：
10.18632/aging.100160
发表时间：
2010-06
期刊：
Aging
影响因子：
--
作者：
Korotchkina LG;Leontieva OV;Bukreeva EI;Demidenko ZN;Gudkov AV;Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
2.1
作者：
Danilova, Nadia;Sakamoto, Kathleen M.;Lin, Shuo
通讯作者：
Lin, Shuo
影响因子：
5.3
作者：
Panic, Linda;Tamarut, Sanda;Volarevic, Sinisa
通讯作者：
Volarevic, Sinisa