A Janus kinase inhibitor, JAB, is an interferon-γ-inducible gene and confers resistance to interferons

Hiroshi Sakamoto, Hideo Yasukawa, Masaaki Masuhara, Shyu Tanimura, Atsuo Sasaki, Kentaro Yuge, Motoaki Ohtsubo, Akira Ohtsuka, Takasi Fujita, Tsunetaka Ohta, Yusuke Furukawa, Satsuki Iwase, Hisashi Yamada, Akihiko Yoshimura

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Abstract

It has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). However, molecular mechanism of regulation of IFN signaling has not been fully understood. We have reported novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. Here we report that JAB is strongly induced by IFN-γ but not by IFN-β in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH-3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-β and IFN-γ. M1 leukemic cells stably expressing JAB were also resistant to IFN-γ and IFN-β-induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-γ did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-γ-induced activation of JAK1 and JAK2 and IFN-β-induced JAK1 and Tyk2 activation were inhibited in NIH-3T3 JAB transformants. These results suggest that JAB inhibits IFN signaling by blocking JAK activity. We also found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STAT1 and JAK phosphorylation was partially reduced. Therefore, overexpression of JAB could be, at least in part, a mechanism of IFN resistance.

Original languageEnglish
Pages (from-to)1668-1676
Number of pages9
JournalBlood
Volume92
Issue number5
Publication statusPublished - 1998 Sep 1
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Sakamoto, H., Yasukawa, H., Masuhara, M., Tanimura, S., Sasaki, A., Yuge, K., Ohtsubo, M., Ohtsuka, A., Fujita, T., Ohta, T., Furukawa, Y., Iwase, S., Yamada, H., & Yoshimura, A. (1998). A Janus kinase inhibitor, JAB, is an interferon-γ-inducible gene and confers resistance to interferons. Blood, 92(5), 1668-1676.