CIS1, a cytokine-inducible SH2 protein, suppresses BCR/ABL-mediated transformation. Involvement of the ubiquitin proteasome pathway.
BCR/ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph)-positive leukemia. A general understanding of BCR/ABL signaling events is emerging, but little is known about the endogenous inhibitors of p210 BCR/ABL. The present study focused attention on CIS1, a ... cytokine-inducible SH2 protein, as a potential physiologic antagonist for BCR/ABL.The murine hematopoietic cell line NSF/N1.H7 stably transfected with BCR/ABL was compared to the parental counterparts for induction of CIS1 by immunoblotting and immunoprecipitation. Cells were treated with a proteasome inhibitor to examine the effect of a proteasome inhibitor on CIS1 protein expression. To determine the effect of CIS1 on BCR/ABL-mediated transformation, we generated Rat-1 fibroblasts transfected with either a control vector, CIS1, BCR/ABL p210, or CIS1 plus BCR/ABL p210.Three forms of CIS1 with molecular masses of 32, 37, and 47 kDa were detected in BCR/ABL-transformed cells. The 47-kDa protein was a ubiquitinated protein. The proteasome inhibitor increased the formation of complexes between CIS1 and BCR/ABL. Transformation of p210 BCR/ABL was significantly suppressed in cells overexpressing CIS1.The results suggest that CIS1 is an endogenous inhibitor of p210 BCR/ABL and is likely to be important in the pathogenesis of Ph-positive leukemia.
Mesh Terms:
3T3 Cells, Animals, Cell Transformation, Neoplastic, Cysteine Endopeptidases, DNA-Binding Proteins, Fibroblasts, Fusion Proteins, bcr-abl, Humans, Immediate-Early Proteins, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Milk Proteins, Molecular Weight, Multienzyme Complexes, Proteasome Endopeptidase Complex, Protein Binding, Protein Isoforms, Protein Processing, Post-Translational, Rats, Recombinant Fusion Proteins, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transfection, Ubiquitins, src Homology Domains
3T3 Cells, Animals, Cell Transformation, Neoplastic, Cysteine Endopeptidases, DNA-Binding Proteins, Fibroblasts, Fusion Proteins, bcr-abl, Humans, Immediate-Early Proteins, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Milk Proteins, Molecular Weight, Multienzyme Complexes, Proteasome Endopeptidase Complex, Protein Binding, Protein Isoforms, Protein Processing, Post-Translational, Rats, Recombinant Fusion Proteins, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transfection, Ubiquitins, src Homology Domains
Exp. Hematol.
Date: Mar. 01, 2001
PubMed ID: 11274764
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- Interactions 3
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