A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons.
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-gamma but not by IFN-beta 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-beta and IFN-gamma. M1 leukemic cells stably expressing JAB were also resistant to IFN-gamma and IFN-beta-induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-gamma did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-gamma-induced activation of JAK1 and JAK2 and IFN-beta-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.
Institute of Life Science, Kurume University, Aikawamachi, Kurume; the Department of Tumor Cell Biology, Tokyo Metropolitan Institute of Medical Science, Bunkyoku, Tokyo, Japan.
H
H
Sakamoto
H
H
Yasukawa
M
M
Masuhara
S
S
Tanimura
A
A
Sasaki
K
K
Yuge
M
M
Ohtsubo
A
A
Ohtsuka
T
T
Fujita
T
T
Ohta
Y
Y
Furukawa
S
S
Iwase
H
H
Yamada
A
A
Yoshimura
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors; D015870:Gene Expression; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007951:Leukemia, Myeloid; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D016899:Interferon-beta; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2