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.

[1]  T. Hirano,et al.  Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. , 1996, The EMBO journal.

[2]  F. Mandelli,et al.  5 The interferons in haematological malignancies , 1994 .

[3]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.

[4]  Tom Maniatis,et al.  Regulation of Interferon-γ-Activated STAT1 by the Ubiquitin-Proteasome Pathway , 1996, Science.

[5]  B. Groner,et al.  Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transmission. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  P. Hersey,et al.  Interferon-resistant Human Melanoma Cells Are Deficient in ISGF3 Components, STAT1, STAT2, and p48-ISGF3γ* , 1997, The Journal of Biological Chemistry.

[7]  A. Ciechanover,et al.  The ubiquitin conjugation system is required for ligand‐induced endocytosis and degradation of the growth hormone receptor. , 1996, The EMBO journal.

[8]  P. Rothman,et al.  IFN-γ represses ε germline transcription and subsequently down-regulates switch recombination to ε , 1994 .

[9]  B. Wines,et al.  Resistance of melanoma cell lines to interferons correlates with reduction of IFN-induced tyrosine phosphorylation. Induction of the anti-viral state by IFN is prevented by tyrosine kinase inhibitors. , 1995, Journal of immunology.

[10]  J. Ihle.  STATs: Signal Transducers and Activators of Transcription , 1996, Cell.

[11]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[12]  C. Schindler,et al.  Functionally distinct isoforms of STAT5 are generated by protein processing. , 1997, Immunity.

[13]  A. Miyajima,et al.  Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. , 1995, The EMBO journal.

[14]  I. Adham,et al.  Sequence analysis of the conserved protamine gene cluster shows that it contains a fourth expressed gene , 1996, Molecular reproduction and development.

[15]  U Klingmüller,et al.  Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T. Hirano,et al.  A central role for Stat3 in IL‐6‐induced regulation of growth and differentiation in M1 leukemia cells. , 1996, The EMBO journal.

[17]  H. Sakamoto,et al.  Cloning and characterization of novel CIS family genes. , 1997, Biochemical and biophysical research communications.

[18]  Takaho A. Endo,et al.  A new protein containing an SH2 domain that inhibits JAK kinases , 1997, Nature.

[19]  J. Darnell,et al.  The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase. , 1996, The EMBO journal.

[20]  R. Coffman,et al.  Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells. , 1995, Science.

[21]  R. Locksley,et al.  CD4+ effector cells default to the Th2 pathway in interferon gamma- deficient mice infected with Leishmania major , 1994, The Journal of experimental medicine.

[22]  山村 康子.  Distinct downstream signaling mechanism between erythropoietin receptor and interleukin-2 receptor , 1994 .

[23]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[24]  H. Fujii.  Activation of Stat5 by interleukin 2 requires a carboxy-terminal region β chain but is not exxential for the proliferative signal transdution. , 1995 .

[25]  S. Nagata,et al.  Functional domains of the granulocyte colony‐stimulating factor receptor. , 1991, The EMBO journal.

[26]  J. Ihle,et al.  Naturally occurring dominant negative variants of Stat5 , 1996, Molecular and cellular biology.

[27]  C. Schindler,et al.  Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF‐1 promoter to mediate induction by IFN alpha and IFN gamma, and is likely to autoregulate the p91 gene. , 1994, The EMBO journal.

[28]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[29]  T. Naka,et al.  Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. , 1997, Biochemical and biophysical research communications.

[30]  T. Maniatis,et al.  Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. , 1996, Science.

[31]  N. Copeland,et al.  A novel cytokine‐inducible gene CIS encodes an SH2‐containing protein that binds to tyrosine‐phosphorylated interleukin 3 and erythropoietin receptors. , 1995, The EMBO journal.

[32]  P Jay,et al.  Specific inhibition of Stat3 signal transduction by PIAS3. , 1997, Science.

[33]  A. Yoshimura,et al.  CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. , 1997, Blood.

[34]  H. Lodish,et al.  Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. , 1990, Proceedings of the National Academy of Sciences of the United States of America.