YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins

EMBO Rep. 2016 Feb;17(2):188-201. doi: 10.15252/embr.201540488. Epub 2015 Dec 21.

Abstract

Mutant p53 proteins are present in more than half of human cancers. Yes-associated protein (YAP) is a key transcriptional regulator controlling organ growth, tissue homeostasis, and cancer. Here, we report that these two determinants of human malignancy share common transcriptional signatures. YAP physically interacts with mutant p53 proteins in breast cancer cells and potentiates their pro-proliferative transcriptional activity. We found YAP as well as mutant p53 and the transcription factor NF-Y onto the regulatory regions of cyclin A, cyclin B, and CDK1 genes. Either mutant p53 or YAP depletion down-regulates cyclin A, cyclin B, and CDK1 gene expression and markedly slows the growth of diverse breast cancer cell lines. Pharmacologically induced cytoplasmic re-localization of YAP reduces the expression levels of cyclin A, cyclin B, and CDK1 genes both in vitro and in vivo. Interestingly, primary breast cancers carrying p53 mutations and displaying high YAP activity exhibit higher expression levels of cyclin A, cyclin B, and CDK1 genes when compared to wt-p53 tumors.

Keywords: gene expression; metabolism; mutant p53 and YAP; proliferation; statin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • CDC2 Protein Kinase
  • Cell Proliferation
  • Cyclin A / genetics
  • Cyclin A / metabolism
  • Cyclin B / genetics
  • Cyclin B / metabolism
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Mutation
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Protein Transport
  • Transcription Factors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cyclin A
  • Cyclin B
  • Phosphoproteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • YAP1 (Yes-associated) protein, human
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases