p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

Cinzia Caprio; Antonio Baldini

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p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

机译：p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

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T-box 1 (Tbx1), a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene in humans causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we found a strong genetic interaction between Tbx1 and transformation related protein 53 (Trp53). Indeed, genetic ablation of Trp53, or pharmacological inhibition of its protein product p53, rescues significantly the cardiovascular defects of Tbx1 heterozygous and hypomorphic mutants. We found that the Tbx1 and p53 proteins do not interact directly but both occupy a genetic element of Gbx2, which is required for aortic arch and cardiac outflow tract development, and is a known genetic interactor of Tbx1.We found that Gbx2 expression is down-regulated in Tbx1~(+/?) embryos and is restored to normal levels in Tbx1~(+/?);Trp53~(+/?) embryos. In addition, we found that the genetic element that binds both Tbx1 and p53 is highly enriched in H3K27 trimethylation, and upon p53 suppression H3K27me3 levels are reduced, along with Ezh2 enrichment. This finding suggests that the rescue of Gbx2 expression in Tbx1~(+/?);Trp53~(+/?) embryos is due to reduction of repressive chromatin marks. Overall our data identify unexpected genetic interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第37期|13385-13390|共6页
作者
Cinzia Caprio; Antonio Baldini;
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作者单位

Open University PhD Program, 80131 Naples, Italy;

Consiglio Nazionale delle Ricerche Institute of Genetics and Biophysics Adriano Buzzati Traverso, 80131 Naples, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Tbx1 and second heart field; pharyngeal arch artery development;

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

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