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J. Biol. Chem., Vol. 277, Issue 34, 30622-30628, August 23, 2002

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Ectopic Expression of Protein-tyrosine Kinase Bcr-Abl Suppresses Tumor Necrosis Factor (TNF)-induced NF-B Activation and IB Phosphorylation
RELATIONSHIP WITH DOWN-REGULATION OF TNF RECEPTORS^*

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

From the Cytokine Research Laboratory, the Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the  Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky 40292, and the ^§ Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

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-B in MO7E cells but not in MBA cells. The impaired NF-B activation in Bcr-Abl-expressing cells was not due to absence of the NF-B proteins p65, p50, or p100 or of IB or IB. Okadaic acid-induced NF-B activation was unaffected by Bcr-Abl expression. TNF induced IB phosphorylation and degradation in MO7E cells but not in MBA cells. The suppression of TNF-induced NF-B 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-B 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.

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