Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor

EMBO J. 2003 Dec 15;22(24):6526-36. doi: 10.1093/emboj/cdg620.

Abstract

Nur77 is a nuclear orphan steroid receptor that has been implicated in negative selection. Expression of Nur77 in thymocytes and cell lines leads to apoptosis through a mechanism that remains unclear. In some cell lines, Nur77 was reported to act through a transcription-independent mechanism involving translocation to mitochondria, leading to cytochrome c release. However, we show here that Nur77-mediated apoptosis in thymocytes does not involve cytoplasmic cytochrome c release and cannot be rescued by Bcl-2. Microarray analysis shows that Nur77 induces many genes, including two novel genes (NDG1, NDG2) and known apoptotic genes FasL and TRAIL. Characterization of NDG1 and NDG2 indicates that NDG1 initiates a novel apoptotic pathway in a Bcl-2-independent manner. Thus Nur77-mediated apoptosis in T cells involves Bcl-2 independent transcriptional activation of several known and novel apoptotic pathways.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Base Sequence
  • Cells, Cultured
  • Cloning, Molecular
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Escherichia coli / cytology
  • Escherichia coli / genetics
  • Escherichia coli / physiology
  • Female
  • Genotype
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Oligonucleotide Array Sequence Analysis
  • Pregnancy
  • Rats
  • Receptors, Antigen, T-Cell / physiology
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcriptional Activation / genetics*

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nr4a1 protein, rat
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Antigen, T-Cell
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors