Tyrosine Phosphorylation of c-Maf Enhances the Expression of IL-4 Gene

Lai, Chen-Yen; Lin, Shin-Ying; Wu, Chia-Kai; Yeh, Li-Tzu; Sytwu, Huey‐Kang; Miaw, Shi‐Chuen

doi:10.4049/jimmunol.1200405

Cited by 18 publications

(23 citation statements)

References 18 publications

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“…27 In MM cells, both c-Maf and MafB can be phosphorylated by the Ser/Thr kinase GSK3, thus increasing MM cell proliferation and colony formation. 28 The ubiquitination of c-Maf could lead to its degradation which could possibly decrease its oncogenicity in MM cells.…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Zhang

Tong

Tang

et al. 2016

Blood

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Key Points• HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation.• HERC4 suppresses MM cell proliferation and delays MM tumor growth.The transcription factor c-Maf is extensively involved in the pathophysiology of multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, affinity chromatography and mass spectrometry were used to identify c-Maf ubiquitination-associated proteins, from which the E3 ligase HERC4 was found to interact with c-Maf and catalyzed its polyubiquitination and subsequent proteasome-mediated degradation. HERC4 mediated polyubiquitination at K85 and K297 in c-Maf, and this polyubiquitination could be prevented by the isopeptidase USP5. Further analysis on the NCI-60 cell line collection revealed that RPMI 8226, a MM-derived cell line, expressed the lowest level of HERC4. Primary bone marrow analysis revealed HERC4 expression was high in normal bone marrow, but was steadily decreased during myelomagenesis. These findings suggested HERC4 played an important role in MM progression. Moreover, ectopic HERC4 expression decreased MM proliferation in vitro, and delayed xenograft tumor growth in vivo. Therefore, modulation of c-Maf ubiquitination by targeting HERC4 may represent a new therapeutic modality for MM. (Blood. 2016;127(13):1676-1686

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Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Zhang

Tong

Tang

et al. 2016

Blood

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“…Furthermore, SATB1 coordinates Th2 cell differentiation by positively regulating Gata3 (Notani et al, 2010). SATB1, NFIL3, MAF, and PPARG positively regulate the gene expression of the Th2 cytokine Il4 (Ribeiro de Almeida et al, 2009;Kashiwada et al, 2011;Lai et al, 2012;da Rocha Junior et al, 2013;Kwon et al, 2014). In addition to the positive effects on Th2 cell differentiation, NFIL3 suppresses Th17 cell development by directly binding and repressing the Rorg promoter .…”

Section: Th2 Cell-specific Tfs Are Positively Regulated By Stat6 and mentioning

confidence: 99%

Data integration for identification of important transcription factors of STAT6-mediated cell fate decisions

et al. 2016

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ABSTRACT. Data integration has become a useful strategy for uncovering new insights into complex biological networks. We studied whether this approach can help to delineate the signal transducer and activator of transcription 6 (STAT6)-mediated transcriptional network driving T helper (Th) 2 cell fate decisions. To this end, we performed an integrative analysis of publicly available RNA-seq data of Stat6-knockout mouse studies together with STAT6 ChIP-seq data and our own gene expression time series data during Th2 cell differentiation. We focused on transcription factors (TFs), cytokines, and cytokine receptors and delineated 59 positively and 41 negatively STAT6-regulated genes, which were used to construct a transcriptional network around STAT6. The network illustrates that important and well-known TFs for Th2 cell differentiation are positively regulated by STAT6 and act either as activators for Th2 cells (e.g., Gata3, Atf3, Satb1, Nfil3, Maf, and Pparg) or as suppressors for other Th cell subpopulations such as Th1 (e.g., Ar), Th17 (e.g., Etv6), or iTreg (e.g., Stat3 and Hif1a) cells. Moreover, our approach reveals 11 TFs (e.g., Atf5, Creb3l2, and Asb2) with unknown functions in Th cell differentiation. This fact together with the observed enrichment of asthma risk genes among those regulated by STAT6 underlines the potential value of the data integration strategy used here. Thus, our results clearly support the opinion that data integration is a useful tool to delineate complex physiological processes.

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“…To evaluate the effects of PD-L1 expression by liver cancer cells on cytotoxic T-cell function, CD8+ T cells were purified from spleens and lymph nodes of 6-to 8-week-old male BALB/c mice using the EasySep Mouse CD4 and CD8a Positive Selection Kit (StemCell Technologies, Vancouver, BC, Canada) and enriched as previously described [25]. The enriched CD4+ and CD8+ T cells were first rested in complete RPMI 1640 medium for 24 h, then co-cultured with parental and PD-L1-expressing BNL-MEA cells in different ratios for cytokine and cell proliferation assays.…”

Section: Exploration Of Immune Modulatory Effects Of Pd-l1 Expressionmentioning

confidence: 99%

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

Lin

Hsu

et al. 2018

Liver Cancer

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Background: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. Methods: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. Results: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. Conclusions: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.

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Tyrosine Phosphorylation of c-Maf Enhances the Expression of IL-4 Gene

Cited by 18 publications

References 18 publications

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Data integration for identification of important transcription factors of STAT6-mediated cell fate decisions

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

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