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The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells

Oncogene volume 20, pages 849–858 (2001)Cite this article

Abstract

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-γ) 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.

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Acknowledgements

The authors are grateful to A Yoshimura (Institute of Life Science, Kurume University, Japan) for providing the Socs expression vectors, to M Chelbi Alix (Institut Universitaire d'Hématologie, Hôpital St Louis, Paris, France) for the IRF1 probe and the LPH (Hôpital Saint-Louis, Paris, France) for art work. This work was supported in part by grants from the Association contre le Cancer (ARC) and from the Fondation de France. R Monni is supported by a Ministère de l'Education Nationale, de la Recherche et des Technologies (MENRT) fellowship and SCR Santos is supported by Praxis XXI.

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Authors and Affiliations

  1. INSERM U434, Centre d'Etude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, Paris, 75010, France

    Richard Monni, Martine Mauchauffe, Roland Berger, Olivier Bernard & Virginie Penard-Lacronique

  2. INSERM U363, Institut Cochin de Génétique Moléculaire (ICGM), Université René Descartes, 27 rue du Faubourg Saint-Jacques, Paris, 75014, France

    Susana Constantino Rosa Santos, Fabrice Gouilleux & Sylvie Gisselbrecht

  3. UMR 146 CNRS, Institut Curie-Section Recherche, Centre Universitaire, 91405, Orsay, France

    Jacques Ghysdael

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Monni, R., Santos, S., Mauchauffe, M. et al. The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. Oncogene 20, 849–858 (2001). https://doi.org/10.1038/sj.onc.1204201

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