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.
authors.affiliation: Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing, 400016, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Lixin
authors.initials: L
authors.lastname: Yang
authors.forename: Shikha
authors.initials: S
authors.lastname: Gaur
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zhang
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Li
authors.forename: Shuya
authors.initials: S
authors.lastname: Hu
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Weng
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011487:Protein Conformation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
keywords: BRCA1; TP53; cisplatin resistance; gain-of-function