Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy

Jie Li, Lixin Yang, Shikha Gaur, Keqiang Zhang, Xiwei Wu, Yate Ching Yuan, Hongzhi Li, Shuya Hu, Yaguang Weng, Yun Yen

研究成果: 雜誌貢獻文章

24 引文 (Scopus)

摘要

Mutation of the tumor suppressor TP53 gene occurs in greater than half of all human cancers. In addition to loss of tumor suppressor function of wild-type TP53, gain-of-function mutations endow cancer cells with more malignant properties. R273 is a mutation hotspot with the p.R273H, p.R273C, and p.R273G variants occurring most commonly in patient samples. To better understand the consequences of these R273 mutations, we constructed cancer cell lines expressing TP53 p.R273H, p.R273C, or p.R273G and explored their characteristics. We found that p.R273H and p.R273C, but not p.R273G, enhanced proliferation, invasion, and drug resistance in vitro. Furthermore, breast cancer susceptibility protein 1 was upregulated by mutant TP53 p.R273H and p.R273C in response to DNA damage and repair. Transcriptional analysis of the TP53-R273 mutants by RNA-seq confirmed that the apoptosis pathway was less active in p.R273H and p.R273C, compared with R273G. Molecular dynamics simulation further revealed that TP53-R273G binds more tightly to DNA than TP53-R273H or TP53-R273C. These findings indicate that mutation of TP53 at a single codon has different effects, and likely clinical implications. p.R273H and p.R273C lead to a more aggressive phenotype than p.R273G. These findings may contribute to future diagnosis and therapy in TP53 mutant cancers.

原文英語
頁(從 - 到)575-584
頁數10
期刊Human Mutation
35
發行號5
DOIs
出版狀態已發佈 - 一月 1 2014

指紋

Mutation
Neoplasms
BRCA1 Protein
p53 Genes
Molecular Dynamics Simulation
Tumor Suppressor Genes
Drug Resistance
Codon
DNA Repair
DNA Damage
RNA
Apoptosis
Phenotype
Cell Line
DNA
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

引用此文

Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy. / Li, Jie; Yang, Lixin; Gaur, Shikha; Zhang, Keqiang; Wu, Xiwei; Yuan, Yate Ching; Li, Hongzhi; Hu, Shuya; Weng, Yaguang; Yen, Yun.

於: Human Mutation, 卷 35, 編號 5, 01.01.2014, p. 575-584.

研究成果: 雜誌貢獻文章

Li, J, Yang, L, Gaur, S, Zhang, K, Wu, X, Yuan, YC, Li, H, Hu, S, Weng, Y & Yen, Y 2014, 'Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy', Human Mutation, 卷 35, 編號 5, 頁 575-584. https://doi.org/10.1002/humu.22528
Li, Jie ; Yang, Lixin ; Gaur, Shikha ; Zhang, Keqiang ; Wu, Xiwei ; Yuan, Yate Ching ; Li, Hongzhi ; Hu, Shuya ; Weng, Yaguang ; Yen, Yun. / Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy. 於: Human Mutation. 2014 ; 卷 35, 編號 5. 頁 575-584.
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title = "Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy",
abstract = "Mutation of the tumor suppressor TP53 gene occurs in greater than half of all human cancers. In addition to loss of tumor suppressor function of wild-type TP53, gain-of-function mutations endow cancer cells with more malignant properties. R273 is a mutation hotspot with the p.R273H, p.R273C, and p.R273G variants occurring most commonly in patient samples. To better understand the consequences of these R273 mutations, we constructed cancer cell lines expressing TP53 p.R273H, p.R273C, or p.R273G and explored their characteristics. We found that p.R273H and p.R273C, but not p.R273G, enhanced proliferation, invasion, and drug resistance in vitro. Furthermore, breast cancer susceptibility protein 1 was upregulated by mutant TP53 p.R273H and p.R273C in response to DNA damage and repair. Transcriptional analysis of the TP53-R273 mutants by RNA-seq confirmed that the apoptosis pathway was less active in p.R273H and p.R273C, compared with R273G. Molecular dynamics simulation further revealed that TP53-R273G binds more tightly to DNA than TP53-R273H or TP53-R273C. These findings indicate that mutation of TP53 at a single codon has different effects, and likely clinical implications. p.R273H and p.R273C lead to a more aggressive phenotype than p.R273G. These findings may contribute to future diagnosis and therapy in TP53 mutant cancers.",
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T1 - Mutants TP53 p.R273H and p.R273C but not p.R273G Enhance Cancer Cell Malignancy

AU - Li, Jie

AU - Yang, Lixin

AU - Gaur, Shikha

AU - Zhang, Keqiang

AU - Wu, Xiwei

AU - Yuan, Yate Ching

AU - Li, Hongzhi

AU - Hu, Shuya

AU - Weng, Yaguang

AU - Yen, Yun

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Mutation of the tumor suppressor TP53 gene occurs in greater than half of all human cancers. In addition to loss of tumor suppressor function of wild-type TP53, gain-of-function mutations endow cancer cells with more malignant properties. R273 is a mutation hotspot with the p.R273H, p.R273C, and p.R273G variants occurring most commonly in patient samples. To better understand the consequences of these R273 mutations, we constructed cancer cell lines expressing TP53 p.R273H, p.R273C, or p.R273G and explored their characteristics. We found that p.R273H and p.R273C, but not p.R273G, enhanced proliferation, invasion, and drug resistance in vitro. Furthermore, breast cancer susceptibility protein 1 was upregulated by mutant TP53 p.R273H and p.R273C in response to DNA damage and repair. Transcriptional analysis of the TP53-R273 mutants by RNA-seq confirmed that the apoptosis pathway was less active in p.R273H and p.R273C, compared with R273G. Molecular dynamics simulation further revealed that TP53-R273G binds more tightly to DNA than TP53-R273H or TP53-R273C. These findings indicate that mutation of TP53 at a single codon has different effects, and likely clinical implications. p.R273H and p.R273C lead to a more aggressive phenotype than p.R273G. These findings may contribute to future diagnosis and therapy in TP53 mutant cancers.

AB - Mutation of the tumor suppressor TP53 gene occurs in greater than half of all human cancers. In addition to loss of tumor suppressor function of wild-type TP53, gain-of-function mutations endow cancer cells with more malignant properties. R273 is a mutation hotspot with the p.R273H, p.R273C, and p.R273G variants occurring most commonly in patient samples. To better understand the consequences of these R273 mutations, we constructed cancer cell lines expressing TP53 p.R273H, p.R273C, or p.R273G and explored their characteristics. We found that p.R273H and p.R273C, but not p.R273G, enhanced proliferation, invasion, and drug resistance in vitro. Furthermore, breast cancer susceptibility protein 1 was upregulated by mutant TP53 p.R273H and p.R273C in response to DNA damage and repair. Transcriptional analysis of the TP53-R273 mutants by RNA-seq confirmed that the apoptosis pathway was less active in p.R273H and p.R273C, compared with R273G. Molecular dynamics simulation further revealed that TP53-R273G binds more tightly to DNA than TP53-R273H or TP53-R273C. These findings indicate that mutation of TP53 at a single codon has different effects, and likely clinical implications. p.R273H and p.R273C lead to a more aggressive phenotype than p.R273G. These findings may contribute to future diagnosis and therapy in TP53 mutant cancers.

KW - BRCA1

KW - Cisplatin resistance

KW - Gain-of-function

KW - TP53

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