In vivo RNA-seq and ChIP-seq analyses show an obligatory role for the C terminus of p53 in conferring tissue-specific radiation sensitivity.
In vivo RNA-seq and ChIP-seq analyses show an obligatory role for the C terminus of p53 in conferring tissue-specific radiation sensitivity.
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DOI：
10.1016/j.celrep.2023.112216
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发表时间：
2023-03-28
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
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以前的研究表明，对辐射的敏感性因组织而异，并取决于肿瘤抑制因子p53。Resnick等人表明，这发生在p53占据基因后的一个步骤，并依赖于其极端的C-末端。与肝脏相反，胸腺和脾脏是放射敏感性组织，其中p53依赖性细胞凋亡在体内全身辐射后被触发。联合RNA测序（RNA-seq）和染色质免疫沉淀测序（ChIP-seq）分析辐射处理的小鼠器官鉴定共享和组织特异性p53转录反应。正如预期的那样，胸腺和脾脏中共有的p53靶标富含凋亡靶标。不能上调肝脏中的这些基因并不是因为基因占有率降低。工程小鼠模型的使用表明，p53的C末端的缺失可以赋予肝脏中p53凋亡靶点的辐射诱导表达，伴随着细胞死亡的增加。全局RNA-seq分析表明，肝脏特异性p53靶点的转录激活也需要C末端的额外作用。据推测，凋亡基因表达的抑制与肝脏特异性靶点的增强激活相结合，赋予组织特异性放射抗性。
Previously it was shown that sensitivity to radiation differs from tissue to tissue and is dependent upon the tumor suppressor p53. Resnick et al. show that this occurs at a step after p53 occupies genes and relies on its extreme C-terminal end. Thymus and spleen, in contrast to liver, are radiosensitive tissues in which p53-dependent apoptosis is triggered after whole-body radiation in vivo. Combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses of radiation-treated mouse organs identifies both shared and tissue-specific p53 transcriptional responses. As expected, the p53 targets shared among thymus and spleen are enriched in apoptotic targets. The inability to upregulate these genes in the liver is not due to reduced gene occupancy. Use of an engineered mouse model shows that deletion of the C terminus of p53 can confer radiation-induced expression of p53 apoptotic targets in the liver with concomitant increased cell death. Global RNA-seq analysis reveals that an additional role of the C terminus is also needed for transcriptional activation of liver-specific p53 targets. It is hypothesized that both suppression of apoptotic gene expression combined with enhanced activation of liver-specific targets confers tissue-specific radio-resistance.
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影响因子：
64.5
作者：
An, W;Kim, J;Roeder, RG
通讯作者：
Roeder, RG
DOI：
10.1038/nsb0901-730
发表时间：
2001-09-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Ahn, J;Prives, C
通讯作者：
Prives, C
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
7.3
作者：
Coates, PJ;Lorimore, SA;Wright, EG
通讯作者：
Wright, EG
影响因子：
8
作者：
Fischer M
通讯作者：
Fischer M