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.
Monni
R
R
INSERM U434, Centre d'Etude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, 75010 Paris, France.
Santos
S C
SC
Mauchauffe
M
M
Berger
R
R
Ghysdael
J
J
Gouilleux
F
F
Gisselbrecht
S
S
Bernard
O
O
Penard-Lacronique
V
V
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D053614:Janus Kinase 2; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014452:Ubiquitins / Q000378:metabolism; D000096743:Interferon gamma Receptor; D000097764:ETS Translocation Variant 6 Protein
D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D016207:Cytokines; D053614:Janus Kinase 2; D009097:Multienzyme Complexes; D015514:Oncogene Proteins, Fusion; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014452:Ubiquitins; D000096743:Interferon gamma Receptor; C491590:Socs1 protein, mouse; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse