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Bcl-X(L) affects Ca(2+) homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Chi Li1, Casey J Fox, Stephen R Master

  • 1Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 16, 2002
PubMed

Insights

Bcl-X(L) protein expression reduces type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R) levels, impacting calcium signaling and cellular stress responses. This suggests Bcl-2 family proteins modulate mitochondrial-nuclear communication.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • The inositol 1,4,5-trisphosphate receptor (IP(3)R) plays a crucial role in intracellular calcium signaling.
  • Bcl-X(L) is a member of the Bcl-2 family of proteins, known for their roles in apoptosis regulation.
  • Mitochondrial function and nuclear gene expression are interconnected through stress-responsive pathways.

Purpose of the Study:

  • To investigate the effect of Bcl-X(L) expression on IP(3)R levels and function.
  • To elucidate the role of the mitochondrion-to-nucleus stress-responsive pathway in regulating IP(3)R.
  • To determine how Bcl-X(L) influences this pathway and its downstream effects on calcium signaling and apoptosis.

Main Methods:

  • Oligonucleotide-based microarray analysis of 9,500 genes and ESTs.
  • Northern and Western blot analyses to confirm mRNA and protein levels.
  • Analysis of transcription factor NFATc2 binding to the IP(3)R promoter.
  • Measurement of T cell antigen receptor ligation-induced Ca(2+) flux.
  • Assessment of IP(3)-mediated Ca(2+) release from microsomal vesicles.
  • Reintroduction of IP(3)R into Bcl-X(L)-transfected cells.

Main Results:

  • Bcl-X(L) expression significantly down-regulated type 1 IP(3)R at mRNA and protein levels in hematopoietic and T cells.
  • Bcl-X(L) decreased the induction of NFATc2 binding to the IP(3)R promoter and subsequent IP(3)R expression under conditions of inhibited mitochondrial oxidative phosphorylation.
  • Bcl-X(L) expression correlated with reduced T cell receptor-induced calcium flux and lower IP(3)-mediated calcium release.
  • Reintroduction of IP(3)R partially reversed the anti-apoptotic effects of Bcl-X(L).

Conclusions:

  • Bcl-X(L) expression suppresses type 1 IP(3)R expression, impacting calcium signaling.
  • Bcl-X(L) interferes with the mitochondrion-to-nucleus stress-responsive pathway regulating IP(3)R.
  • Bcl-2 family proteins influence signaling networks linking mitochondrial metabolism to nuclear gene expression, even in non-apoptotic conditions.

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