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p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos
The p53 is one of the most important tumor suppressors through surveillance of DNA damages and abnormal proliferation signals, and activation the cell cycle arrest and apoptosis in response to stress. However, the mutation of p53 is known to be oncogenic by both loss of function in inhibiting cell c...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743294/ https://www.ncbi.nlm.nih.gov/pubmed/31523200 http://dx.doi.org/10.7150/ijbs.31451 |
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author | Zhao, Jinzhi Tian, Yingbing Zhang, Huihui Qu, Lianhua Chen, Yu Liu, Qing Luo, Ying Wu, Xiaoming |
author_facet | Zhao, Jinzhi Tian, Yingbing Zhang, Huihui Qu, Lianhua Chen, Yu Liu, Qing Luo, Ying Wu, Xiaoming |
author_sort | Zhao, Jinzhi |
collection | PubMed |
description | The p53 is one of the most important tumor suppressors through surveillance of DNA damages and abnormal proliferation signals, and activation the cell cycle arrest and apoptosis in response to stress. However, the mutation of p53 is known to be oncogenic by both loss of function in inhibiting cell cycle progress and gain of function in promoting abnormal proliferation. In the present study, we have established a knock in mouse model containing an Asn-to-Ser substitution at p53 amino acid 236 by homologous recombination (p53N236S). Other than tumorigenesis phenotype, we found that p53(S/S)mice displayed female-specific phenotype of open neural tube in brain (exencephaly) and spinal cord (spina bifida). The occurrence rate for embryonic exencephaly is 68.5% in female p53(S/S) mice, which is much more than that of in p53(-/-) mice (37.1%) in the same genetic background. Further study found that p53(N236S) mutation increased neuronal proliferation and decreased neuronal differentiation and apoptosis. To rescue the phenotype, we inhibited cell proliferation by crossing Wrn(-/-)mice with p53(S/S) mice. The occurrence of NTDs in p53(S/S) Wrn(-/-)mice was 35.2%, thus suggesting that the inhibition of cell proliferation through a Wrn defect partially rescued the exencephaly phenotype in p53(S/S) mice. We also report that p53S decreased expression of UTX at mRNA and protein level via increasing Xist transcript, result in high female-specific H3K27me3 expression and repressed Mash1 transcription, which facilitating abnormal proliferation, differentiation, and apoptosis, result in the mis-regulation of neurodevelopment and neural tube defects (NTDs). |
format | Online Article Text |
id | pubmed-6743294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-67432942019-09-14 p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos Zhao, Jinzhi Tian, Yingbing Zhang, Huihui Qu, Lianhua Chen, Yu Liu, Qing Luo, Ying Wu, Xiaoming Int J Biol Sci Research Paper The p53 is one of the most important tumor suppressors through surveillance of DNA damages and abnormal proliferation signals, and activation the cell cycle arrest and apoptosis in response to stress. However, the mutation of p53 is known to be oncogenic by both loss of function in inhibiting cell cycle progress and gain of function in promoting abnormal proliferation. In the present study, we have established a knock in mouse model containing an Asn-to-Ser substitution at p53 amino acid 236 by homologous recombination (p53N236S). Other than tumorigenesis phenotype, we found that p53(S/S)mice displayed female-specific phenotype of open neural tube in brain (exencephaly) and spinal cord (spina bifida). The occurrence rate for embryonic exencephaly is 68.5% in female p53(S/S) mice, which is much more than that of in p53(-/-) mice (37.1%) in the same genetic background. Further study found that p53(N236S) mutation increased neuronal proliferation and decreased neuronal differentiation and apoptosis. To rescue the phenotype, we inhibited cell proliferation by crossing Wrn(-/-)mice with p53(S/S) mice. The occurrence of NTDs in p53(S/S) Wrn(-/-)mice was 35.2%, thus suggesting that the inhibition of cell proliferation through a Wrn defect partially rescued the exencephaly phenotype in p53(S/S) mice. We also report that p53S decreased expression of UTX at mRNA and protein level via increasing Xist transcript, result in high female-specific H3K27me3 expression and repressed Mash1 transcription, which facilitating abnormal proliferation, differentiation, and apoptosis, result in the mis-regulation of neurodevelopment and neural tube defects (NTDs). Ivyspring International Publisher 2019-07-25 /pmc/articles/PMC6743294/ /pubmed/31523200 http://dx.doi.org/10.7150/ijbs.31451 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Zhao, Jinzhi Tian, Yingbing Zhang, Huihui Qu, Lianhua Chen, Yu Liu, Qing Luo, Ying Wu, Xiaoming p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos |
title | p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos |
title_full | p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos |
title_fullStr | p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos |
title_full_unstemmed | p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos |
title_short | p53 Mutant p53(N236S) Induces Neural Tube Defects in Female Embryos |
title_sort | p53 mutant p53(n236s) induces neural tube defects in female embryos |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743294/ https://www.ncbi.nlm.nih.gov/pubmed/31523200 http://dx.doi.org/10.7150/ijbs.31451 |
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