The anti-proliferative effects of type I IFN involve STAT6-mediated regulation of SP1 and BCL6

Hsu, Yu An; Huang, Chi‐Cheng; Kung, Yung Jen; Lin, Hui Ju; Chang, Chia‐Chu; Lee, Kuan Rong; Wan, Lei

doi:10.1016/j.canlet.2016.02.047

Cited by 20 publications

(12 citation statements)

References 52 publications

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“…Activation of STAT6 results in the formation of a STAT2⅐STAT6 complex in response to IFN-1 stimulation as detected in B cells and is suggested to take part in the IFN-1mediated antiproliferative activity (70). Similarly, it was recently suggested that STAT6, in a STAT2-dependent manner, exerts antiproliferative activity also in Daudi cells upon IFN-1 induction (81).…”

Section: Non-canonical Ifn-1-mediated Signalingmentioning

confidence: 80%

The molecular basis for differential type I interferon signaling

Schreiber

2017

Journal of Biological Chemistry

191

184

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Type I interferons (IFN-1) are cytokines that affect the expression of thousands of genes, resulting in profound cellular changes. IFN-1 activates the cell by dimerizing its two-receptor chains, IFNAR1 and IFNAR2, which are expressed on all nucleated cells. Despite a similar mode of binding, the different IFN-1s activate a spectrum of activities. The causes for differential activation may stem from differences in IFN-1-binding affinity, duration of binding, number of surface receptors, induction of feedbacks, and cell type-specific variations. All together these will alter the signal that is transmitted from the extracellular domain inward. The intracellular domain binds, directly or indirectly, different effector proteins that transmit signals. The composition of effector molecules deviates between different cell types and tissues, inserting an additional level of complexity to the system. Moreover, IFN-1s do not act on their own, and clearly there is much cross-talk between the activated effector molecules by IFN-1 and other cytokines. The outcome generated by all of these factors (processing step) is an observed phenotype, which can be the transformation of the cell to an antiviral state, differentiation of the cell to a specific immune cell, senescence, apoptosis, and many more. IFN-1 activities can be divided into robust and tunable. Antiviral activity, which is stimulated by minute amounts of IFN-1 and is common to all cells, is termed robust. The other activities, which we term tunable, are cell type-specific and often require more stringent modes of activation. In this review, I summarize the current knowledge on the mode of activation and processing that is initiated by IFN-1, in perspective of the resulting phenotypes.

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Section: Non-canonical Ifn-1-mediated Signalingmentioning

confidence: 80%

The molecular basis for differential type I interferon signaling

Schreiber

2017

Journal of Biological Chemistry

191

184

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“…The antiproliferative activity was dose dependent. The biological activity of interferon type I occurs through the IFNAR1 and IFNAR2 receptors [34,35]. The two receptor-associated tyrosine kinases Tyk2 and Jak1 will be activated, which subsequently recruit and activate the cytoplasmic factors belonging to the signal transducer and activator of transcription (STAT) family of proteins [36,37].…”

Section: Resultsmentioning

confidence: 99%

Development of Higher Molecular Weight of Recombinant Human Interferon Alpha-2a by Albumin Fusion Technology in Methilotropic Yeast Pichia Pastoris

Ningrum

Herawati

Wardiana

2017

International Journal on Advanced Science, Engineering and Information Technology

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Human interferon alpha-2a (hIFNα-2a) is a therapeutic protein that used in cancer and hepatitis B/C treatments. One main problem of using hIFNα-2a is the lack of good pharmacokinetic profile due to its low molecular weight. This research aims to develop recombinant hIFNα-2a fusion protein by using human serum albumin (HSA) to improve its molecular weight. The codon optimized open reading frame (ORF) encoding fusion protein constructed synthetically and inserted into pPICZαB expression vector and transformed into Escherichia coli XL1-blue. The characterized recombinant plasmid was linearized and transformed into methilotropic yeast Pichia pastoris GS115 and SMD 1168. The expression analysis showed that the best expression was achieved by protease deficient strain SMD1168. Molecular weight characterization informed that the fusion protein was 85 kDa in size as its theoritical size. Western blotting methods confirmed the identity of fusion protein based on the recognition by anti HSA and anti hIFNα-2 antibodies. This result strongly indicated that the fusion protein was successfully produced in Pichia pastoris. Protein quantification informed that the protein yield was 14 mg/L (OD600=2). Stability expression analysis showed that protein production was stable until 60 th generations. Preliminary antiproliverative activity assay demonstrated that the fusion protein had 20% lower activity comparing to non fusion form.

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“…Chromatin immunoprecipitation (ChIP) was performed as previously described elsewhere . The treated cells were cross‐linked using 1% formaldehyde, lysed and sonicated in a Covaris instrument (shearing time 30 min, 20% duty cycle, intensity 10, 200 cycles per burst, 30 seconds per cycle) in 2 ml.…”

Section: Methodsmentioning

confidence: 99%

Deceleration of glycometabolism impedes IgG‐producing B‐cell‐mediated tumor elimination by targeting SATB1

Liu

Zhou

et al. 2018

Immunology

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B lymphocytes, known as antibody producers, mediate tumor cell destruction in the manner of antibody-dependent cell-mediated cytotoxicity; however, their anti-tumor function seems to be weakened during tumorigenesis, while the underlying mechanisms remain unclear. In this study, we found that IgG mediated anti-tumor effects, but IgG-producing B cells decreased in various tumors. Considering the underlying mechanism, glycometabolism was noteworthy. We found that tumor-infiltrating B cells were glucose-starved and accompanied by a deceleration of glycometabolism. Both inhibition of glycometabolism and deprivation of glucose through tumor cells, or glucose-free treatment, reduced the differentiation of B cells into IgG-producing cells. In this process, special AT-rich sequence-binding protein-1 (SATB1) was significantly silenced in B cells. Down-regulating SATB1 by inhibiting glycometabolism or RNA interference reduced the binding of signal transducer and activator of transcription 6 (STAT6) to the promoter of germline Cγ gene, subsequently resulting in fewer B cells producing IgG. Our findings provide the first evidence that glycometabolic inhibition by tumorigenesis suppresses differentiation of B cells into IgG-producing cells, and altering glycometabolism may be promising in improving the anti-tumor effect of B cells.

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The anti-proliferative effects of type I IFN involve STAT6-mediated regulation of SP1 and BCL6

Cited by 20 publications

References 52 publications

The molecular basis for differential type I interferon signaling

The molecular basis for differential type I interferon signaling

Development of Higher Molecular Weight of Recombinant Human Interferon Alpha-2a by Albumin Fusion Technology in Methilotropic Yeast Pichia Pastoris

Deceleration of glycometabolism impedes IgG‐producing B‐cell‐mediated tumor elimination by targeting SATB1

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