Ectopic expression of protein-tyrosine kinase Bcr-Abl suppresses tumor necrosis factor (TNF)-induced NF-κB activation and IκBα phosphorylation: Relationship with down-regulation of TNF receptors

Asok Mukhopadhyay, Shishir Shishodia, Jill Suttles, Katherine Brittingham, Betty Lamothe, Ramdevi Nimmanapalli, Kapil N. Bhalla, Bharat B. Aggarwal

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Bcr-Abl, the product of the protooncogene bcr-abl, is a constitutively active protein-tyrosine kinase that is highly expressed in chronic myelogenous leukemia and in acute myeloid leukemia cells. Because Bcr-Abl is known to provide mitogenic signals through suppression of apoptosis, we investigated the effect of this oncogene product on signaling by tumor necrosis factor (TNF), a proapoptotic cytokine. We used a bcr-abl-deficient human megakaryocytic leukemia cell line MO7E and an isogenic MBA cell line stably transfected with bcr-abl. Electrophoretic mobility shift assay revealed that TNF activated the nuclear transcription factor NF-κB in MO7E cells but not in MBA cells. The impaired NF-κB activation in Bcr-Abl-expressing cells was not due to absence of the NF-κB proteins p65, p50, or p100 or of IκBα or IκBβ. Okadaic acid-induced NF-κB activation was unaffected by Bcr-Abl expression. TNF induced IκBα phosphorylation and degradation in MO7E cells but not in MBA cells. The suppression of TNF-induced NF-κB activation by Bcr-Abl was not restricted to MBA cells, because ectopic expression of Bcr-Abl in human acute myeloid leukemia HL-60 cells also blocked TNF-induced NF-κB activation. When examined for the TNF receptors by the radioreceptor assay, flow cytometry, or Western blot analysis, we found that Bcr-Abl expression down-regulated the expression of the TNF receptors. The RNase protection assay and Northern blot analysis revealed the transcriptional down-regulation of the TNF receptor by Bcr-Abl protein. Overall, these results indicate that ectopic expression of Bcr-Abl interferes with the TNF signaling pathway through the down-regulation of TNF receptors.

Original languageEnglish (US)
Pages (from-to)30622-30628
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number34
DOIs
StatePublished - Aug 23 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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