The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells.
The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression ... of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.
Mesh Terms:
Animals, B-Lymphocytes, Carrier Proteins, Cell Line, Transformed, Cells, Cultured, Cysteine Endopeptidases, Cytokines, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Janus Kinase 2, Mice, Multienzyme Complexes, Oncogene Proteins, Fusion, Proteasome Endopeptidase Complex, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, Interferon, Repressor Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Ubiquitins
Animals, B-Lymphocytes, Carrier Proteins, Cell Line, Transformed, Cells, Cultured, Cysteine Endopeptidases, Cytokines, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Janus Kinase 2, Mice, Multienzyme Complexes, Oncogene Proteins, Fusion, Proteasome Endopeptidase Complex, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, Interferon, Repressor Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Ubiquitins
Oncogene
Date: Feb. 15, 2001
PubMed ID: 11314018
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