The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense

Cell Rep. 2013 May 30;3(5):1663-77. doi: 10.1016/j.celrep.2013.04.020. Epub 2013 May 16.

Abstract

The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell-cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced glutathione depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects against acetaminophen-induced liver injury. Similar to its effects on YAP, Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetaminophen / pharmacology
  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • GA-Binding Protein Transcription Factor / antagonists & inhibitors
  • GA-Binding Protein Transcription Factor / genetics
  • GA-Binding Protein Transcription Factor / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Hepatocyte Growth Factor / deficiency
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Antioxidants
  • Cell Cycle Proteins
  • GA-Binding Protein Transcription Factor
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • YY1AP1 protein, human
  • macrophage stimulating protein
  • Acetaminophen
  • Hepatocyte Growth Factor
  • LATS1 protein, human
  • STK3 protein, human
  • Protein-Serine-Threonine Kinases