Apoptotic histone modification inhibits nuclear transport by regulating RCC1

Nat Cell Biol. 2009 Jan;11(1):36-45. doi: 10.1038/ncb1810. Epub 2008 Dec 7.

Abstract

A number of signalling pathways have been identified that regulate apoptosis, but the mechanism that initiates apoptosis remains incompletely understood. We have found that the nuclear RanGTP level is diminished during the early stages of apoptosis, which correlates with immobilization of RCC1 on the chromosomes. Furthermore, the expression of phosphomimetic histone H2B or caspase-activated Mst1 immobilizes RCC1 and causes reduction of nuclear RanGTP levels, which leads to inactivation of the nuclear transport machinery. As a consequence, nuclear localization signal (NLS)-containing proteins, including NF-kappaB-p65, remain bound to importins alpha and beta in the cytoplasm. Knocking down Mst1 allows resumption of nuclear transport and the nuclear entry of NF-kappaB-p65, which have important roles in rescuing cells from apoptosis. Therefore, we propose that RCC1 reads the histone code created by caspase-activated Mst1 to initiate apoptosis by reducing the level of RanGTP in the nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics*
  • Apoptosis / genetics*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / ultrastructure
  • Chromosomes / genetics
  • Chromosomes / metabolism
  • Down-Regulation / genetics
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Karyopherins / genetics
  • Karyopherins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • ran GTP-Binding Protein / genetics
  • ran GTP-Binding Protein / metabolism*

Substances

  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • Histones
  • Karyopherins
  • Nuclear Proteins
  • RCC1 protein, human
  • RNA, Small Interfering
  • Transcription Factor RelA
  • STK4 protein, human
  • Protein-Serine-Threonine Kinases
  • ran GTP-Binding Protein