TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73

Kang Liu, Shiyun Ling, Weei Chin Lin

Research output: Contribution to journalArticle

69 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4464-4481
Number of pages18
JournalMolecular and cellular biology
Volume31
Issue number22
DOIs
StatePublished - Nov 1 2011

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Neoplasms
Noxae
Genes
Cyclin A
Heterografts
Up-Regulation
Down-Regulation
Neoplasm Metastasis
Mutation
Therapeutics
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73. / Liu, Kang; Ling, Shiyun; Lin, Weei Chin.

In: Molecular and cellular biology, Vol. 31, No. 22, 01.11.2011, p. 4464-4481.

Research output: Contribution to journalArticle

Liu, Kang ; Ling, Shiyun ; Lin, Weei Chin. / TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73. In: Molecular and cellular biology. 2011 ; Vol. 31, No. 22. pp. 4464-4481.
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