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Arsenic inhibition of the JAK-STAT pathway

Oncogene volume 23, pages 3603–3612 (2004)Cite this article

Abstract

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. Chronic exposure to arsenic has been found to cause immunotoxicity and has been associated with the suppression of hematopoiesis (anemia and leukopenia). Here, we report the novel finding of arsenic-mediated inactivation of the JAK-STAT signaling pathway by its direct interaction with JAK tyrosine kinase. Pretreatment with sodium arsenite strongly inhibited IL-6-inducible STAT3 tyrosine phosphorylation in HepG2 cells and did not affect its serine phosphorylation. As a result, sodium arsenite completely abolished STAT activity-dependent expression of suppressors of cytokine signaling (SOCS). Both cellular and subcelluar experiments showed that the inhibition of JAK-STAT signaling resulted from JAK tyrosine kinase's direct interaction with arsenite, and that arsenic's suppression of JAK tyrosine kinase activity also occurred in the interferon γ (IFNγ) pathway. The ligand-independent inhibition by arsenic indicates that JAK was the direct target of arsenic action. Other inflammatory stimulants, stress agents, and metal cadmium failed to induce similar effects on the tyrosine phosphorylation of STAT3 as arsenic does. Our experiments also revealed that arsenic inactivation of the JAK-STAT pathway occurred independent of arsenic activation of MAP kinases. Taken together, our findings indicate that arsenic directly inhibits JAK tyrosine kinase activity and suggest that this direct interference in the JAK-STAT pathway may play a role in arsenic-associated pathogenesis.

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Acknowledgements

We thank Drs Olivier Bernard and Virginie Penard-Lacronique (U434 Inserm-CEPH, 27 rue Juliette Dodu, 75010 Paris, France) for providing stable BaF3 cell lines expressing Tel-Jak fusion proteins.Supported by NIH Grant ES 10389 (to MWL).

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Authors and Affiliations

  1. Department of Pathology, Baylor College of Medicine, One Baylor Olazam Houston, 77030, TX, USA

    Haiyun Y Cheng & Michael W Lieberman

  2. Department of Medicine, Baylor College of Medicine, Houston, 77030, TX, USA

    Ping Li & Lili Feng

  3. Division of Biology and UCSD Cancer Center, University of California at San Diego, La Jolla, 92093, CA, USA

    Michael David

  4. Molecular Genetics & Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, 15261, PA, USA

    Thomas E Smithgall

  5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, TX, USA

    Michael W Lieberman

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  1. Haiyun Y Cheng
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Correspondence to Michael W Lieberman.

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Cheng, H., Li, P., David, M. et al. Arsenic inhibition of the JAK-STAT pathway. Oncogene 23, 3603–3612 (2004). https://doi.org/10.1038/sj.onc.1207466

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