期刊
CANCER SCIENCE
卷 109, 期 6, 页码 1876-1888出版社
WILEY
DOI: 10.1111/cas.13612
关键词
beta-catenin; invasion; p53; p53(R175H); plakoglobin
类别
资金
- Cathy and Harold Roozen Entrance Scholarship
- Canadian Breast Cancer Foundation Prairies/NWT Chapter
- Lois Hole Hospital for Women through the Women and Children's Health Research Institute
- Dr. Herbert Meltzer Memorial Fellowship
- Andrew Stewart Memorial Graduate Prize
Tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins have not only lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53(R175H)) with well-documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signaling protein and a paralog of -catenin. Unlike -catenin that has oncogenic function through its role in the Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor. We have shown that plakoglobin interacted with wild type and a number of p53 mutants in various carcinoma cell lines. Plakoglobin and mutant p53 interacted with the promoter and regulated the expression of several p53 target genes. Furthermore, plakoglobin interactions with p53 mutants restored their tumor suppressor/metastasis activities invitro. GOF p53 mutants induce accumulation and oncogenic activation of -catenin. Previously, we showed that one mechanism by which plakoglobin may suppress tumorigenesis is by sequestering -catenin's oncogenic activity. Here, we examined the effects of p53(R175H) expression on -catenin accumulation and transcriptional activation and their modifications by plakoglobin coexpression. We showed that p53(R175H) expression in plakoglobin null cells increased total and nuclear levels of -catenin and its transcriptional activity. Coexpression of plakoglobin in these cells promoted -catenin's proteasomal degradation, and decreased its nuclear levels and transactivation. Wnt/-catenin targets, c-MYC and S100A4 were upregulated in p53(R175H) cells and were downregulated when plakoglobin was coexpressed. Plakoglobin-p53(R175H) cells also showed significant reduction in their migration and invasion invitro.
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