A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis

Cell Rep. 2020 Oct 20;33(3):108284. doi: 10.1016/j.celrep.2020.108284.

Abstract

The Hippo signaling pathway maintains organ size and tissue homeostasis via orchestration of cell proliferation and apoptosis. How this pathway triggers cell apoptosis remains largely unexplored. Here, we identify NR4A1 as a target of the Hippo pathway that mediates the pro-apoptotic and anti-tumor effects of the Hippo pathway whereby YAP regulates the transcription, phosphorylation, and mitochondrial localization of NR4A1. NR4A1, in turn, functions as a feedback inhibitor of YAP to promote its degradation, thereby inhibiting the function of YAP during liver regeneration and tumorigenesis. Our studies elucidate a regulatory loop between NR4A1 and YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis and highlight NR4A1 as a marker of Hippo signaling, as well as a therapeutic target for hepatocellular carcinoma.

Keywords: Hippo signaling pathway; NR4A1; apoptosis; hepatocellular carcinoma (HCC); liver regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis / physiology
  • Carcinogenesis
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Female
  • Homeostasis / physiology
  • Humans
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phosphorylation
  • Signal Transduction / drug effects
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Trans-Activators
  • Transcription Factors
  • YAP-Signaling Proteins
  • YY1AP1 protein, human
  • Yap1 protein, mouse