Autocrine secretion of osteopontin results in degradation of I kappa B in Bcr-Abl-expressing cells.
Osteopontin has been identified as a marker of metastasis formation and its increased expression has been correlated with the malignancy of cancer. In this study we provide evidence that increased expression of osteopontin may also be associated with progression of Bcr-Abl-expressing leukaemia cells. The Bcr-Abl fusion protein, generated by the Philadelphia translocation, is the hallmark of chronic myeloid leukaemia (CML). CML exhibits clinically distinct phases. Advanced disease shows defective differentiation, bone marrow infiltration and drug resistance. The critical signalling mediating this disease progression is unknown. Increased aggressiveness of the disease has been correlated with elevated amounts of Bcr-Abl. We generated a 32D cell line model to study the consequences of different expression levels of Bcr-Abl. Osteopontin was identified by microarray analysis as highly upregulated in cells expressing elevated amounts of Bcr-Abl. Moreover, in high Bcr-Abl expressing cells, an additional 50 kDa isoform of osteopontin was detected. It was found that this protein was secreted and that myeloid progenitor cells also expressed appropriate receptors for autocrine activation. We demonstrated that secretion of osteopontin resulted in enhanced degradation of I kappa B, the inhibitor of NF-kappa B. These data indicate a novel consequence of elevated Bcr-Abl expression, which may contribute to the progression of CML.
Vejda
Susanne
S
Cell Development and Disease Laboratory, Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.
Piwocka
Katarzyna
K
McKenna
Sharon L
SL
Cotter
Thomas G
TG
D000818:Animals; D019898:Autocrine Communication; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020672:I-kappa B Proteins / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D051379:Mice; D053495:Osteopontin; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D020672:I-kappa B Proteins; D020033:Protein Isoforms; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D016044:Fusion Proteins, bcr-abl