Endoplasmic reticulum stress initiates apoptotic death induced by STI571 inhibition of p210 bcr-abl tyrosine kinase

Leuk Res. 2004 Feb;28(2):191-202. doi: 10.1016/s0145-2126(03)00218-2.

Abstract

The endoplasmic reticulum (ER) is the site where proteins destined to either secretion or different subcellular compartments assemble and the major storage of intracellular Ca(2+). The ER stress resulting from a variety of toxic insults leads to apoptosis. Here, we showed that the apoptotic death triggered by STI571, an inhibitor of the p210 bcr-abl tyrosine kinase, in murine myeloid progenitors transducing the p210 bcr-abl tyrosine kinase of Chronic Myeloid Leukemia (CML) proceeds from ER stress. The Bcl-2 dowmodulation and inactivation induced by the binding to its antagonist: Bad, the release of caspase 12 from the ER membranes in its active form and of Ca(2+) from the ER pool addressed towards ER a sensor of STI571-induced pro-apoptotic signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Benzamides
  • Calcium / metabolism
  • Caspase 12
  • Caspases / metabolism
  • Cell Line, Transformed
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology*
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Gene Expression Regulation, Neoplastic
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Mutation
  • Phosphorylation
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Pyrimidines / pharmacology*
  • Temperature
  • Transduction, Genetic

Substances

  • Benzamides
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Casp12 protein, mouse
  • Caspase 12
  • Caspases
  • Calcium