Reduction of Bcr-Abl function leads to erythroid differentiation of K562 cells via downregulation of ERK

A. Brózik, N. P. Casey, Cs Hegedus, A. Bors, A. Kozma, H. Andrikovics, M. Geiszt, K. Német, Maria Magócsi

Research output: Chapter in Book/Report/Conference proceedingConference contribution

10 Citations (Scopus)

Abstract

The chimeric bcr-abl gene encodes a constitutively active tyrosine kinase that leads to abnormal transduction of growth and survival signals leading to chronic myeloid leukemia (CML). According to our previous observations, in vitro differentiation of several erythroid cell lines is accompanied by the downregulation of extracellular signal-regulated kinases (ERK)1/2 mitogen-activated protein kinase (MAPK) activities. In this work we investigated whether ERKs have a decisive role in either the erythroid differentiation process or apoptosis of bcr-abl+ K562 cells by means of direct (MEK1/2 inhibitor UO126) and indirect (reduced Bcr-Abl function) inhibition of their activities. We found that both Gleevec and UO126 induced hemoglobin expression. Gleevec treatment reduced the phosphorylation of Bcr-Abl, ERK and STAT-5 for up to 24 h, decreased Bcl-XL levels, and induced caspase-3-dependent apoptosis. In contrast, UO126 treatment resulted in only a transient decrease of ERK activity and did not induce cell death. For studying the effect of reduced Bcr-Abl function on erythroid differentiation at the level of the bcr-abl transcript,we applied the siRNAapproach. Stable degradation of bcr-abl mRNA was achieved by using a retroviral vector with enhanced green fluorescent protein (EGFP) reporter. Despite a high (>90%) transduction efficiency we detected only a transient decrease in Bcr-Abl protein and in phosphorylated ERK1/2 levels. This transient change in Bcr-Abl signaling was sufficient to induce hemoglobin expression without significant cell death. These results suggest that by transiently reducing Bcr-Abl function it is possible to overcome the differentiation blockade without evoking apoptosis in CML cells and that reduced ERK activity may have a crucial role in this process.

Original languageEnglish
Title of host publicationSignal Transduction Pathways, Part A
Subtitle of host publicationApoptotic and Extracellular Signalling
PublisherBlackwell Publishing Inc.
Pages344-354
Number of pages11
ISBN (Print)1573316458, 9781573316453
DOIs
Publication statusPublished - Dec 2006

Publication series

NameAnnals of the New York Academy of Sciences
Volume1090
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

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Keywords

  • Apoptosis
  • Bcr-abl
  • CML
  • Erythroid differentiation
  • MEK/ERK MAPK pathway
  • Stable RNA interference

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Brózik, A., Casey, N. P., Hegedus, C., Bors, A., Kozma, A., Andrikovics, H., Geiszt, M., Német, K., & Magócsi, M. (2006). Reduction of Bcr-Abl function leads to erythroid differentiation of K562 cells via downregulation of ERK. In Signal Transduction Pathways, Part A: Apoptotic and Extracellular Signalling (pp. 344-354). (Annals of the New York Academy of Sciences; Vol. 1090). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1378.038