Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1

Curr Biol. 2000 Oct 5;10(19):1201-4. doi: 10.1016/s0960-9822(00)00728-4.

Abstract

Cell death is regulated mainly through an evolutionarily conserved form of cell suicide termed apoptosis [1]. Deregulation of apoptosis has been associated with cancer, autoimmune diseases and degenerative disorders. Many cells, particularly those of the hematopoietic system, have a default program of cell death and survival that is dependent on the constant supply of survival signals. The Bcl-2 family, which has both pro- and anti-apoptotic members, plays a critical role in regulating cell survival [2]. One family member, the Bcl-2 interacting mediator of cell death (Bim), contains only a protein-interaction motif known as the BH3 domain, allowing it to bind pro-survival Bcl-2 molecules, neutralizing their function [3]. Disruption of the bim gene results in resistance to apoptosis following cytokine withdrawal in leukocytes, indicating that regulation of the pro-apoptotic activity of Bim is critical for maintenance of the default apoptotic program [4]. Here, we report that withdrawal of cytokine results in upregulation of Bim expression concomitant with induction of the apoptotic program in lymphocytes. Activation of the forkhead transcription factor FKHR-L1, previously implicated in regulation of apoptosis in T lymphocytes [5], was sufficient to induce Bim expression. We propose a mechanism by which cytokines promote lymphocyte survival by inhibition of FKHR-L1, preventing Bim expression.

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Bcl-2-Like Protein 11
  • Carrier Proteins / genetics*
  • Cell Line
  • DNA-Binding Proteins / physiology*
  • Membrane Proteins*
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins*
  • Transcription Factors / physiology*

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Carrier Proteins
  • DNA-Binding Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors