Abstract
Nearly half of human cancers harbor p53 mutations, which can promote cancerous growth, metastasis, and resistance to therapy. The gain of function of mutant p53 is partly mediated by its ability to form a complex with NF-Y or p63/p73. Here, we demonstrate that TopBP1 mediates these activities in cancer, and we provide both in vitro and in vivo evidence to support its role. We show that TopBP1 interacts with p53 hot spot mutants and NF-YA and promotes mutant p53 and p300 recruitment to NF-Y target gene promoters. TopBP1 also facilitates mutant p53 interaction with and inhibition of the transcriptional activities of p63/p73. Depletion of TopBP1 in mutant p53 cancer cells leads to downregulation of NF-Y target genes cyclin A and Cdk1 and upregulation of p63/p73 target genes such as Bax and Noxa. Mutant p53-mediated resistance to chemotherapeutic agents depends on TopBP1. The growth-promoting activity of mutant p53 in a xenograft model also requires TopBP1. Thus, TopBP1 mediates mutant p53 gain of function in cancer. Since TopBP1 is often overexpressed in cancer cells and is recruited to cooperate with mutant p53 for tumor progression, TopBP1/mutant p53 interaction may be a new therapeutic target in cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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CCAAT-Binding Factor / metabolism*
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CDC2 Protein Kinase / biosynthesis
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Carrier Proteins / metabolism*
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Cell Line
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Cell Proliferation
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Cyclin A / biosynthesis
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DNA Replication
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DNA-Binding Proteins / metabolism*
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E1A-Associated p300 Protein / metabolism
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Humans
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Membrane Proteins / metabolism*
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Mice
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Mice, Nude
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Mutation
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Neoplasm Transplantation
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Neoplasms / metabolism
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Nuclear Proteins / metabolism*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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RNA Interference
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RNA, Small Interfering
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Transcription, Genetic
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Transcriptional Activation
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Transplantation, Heterologous
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Tumor Protein p73
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / metabolism*
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bcl-2-Associated X Protein / biosynthesis
Substances
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CCAAT-Binding Factor
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CKAP4 protein, human
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Carrier Proteins
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Cyclin A
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DNA-Binding Proteins
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Membrane Proteins
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Nuclear Proteins
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PMAIP1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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TOPBP1 protein, human
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TP53 protein, human
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TP73 protein, human
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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E1A-Associated p300 Protein
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EP300 protein, human
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CDC2 Protein Kinase