The Roles of Synoviolin in Crosstalk Between Endoplasmic Reticulum Stress-Induced Apoptosis and p53 Pathway

Yamasaki, Satoshi; Yagishita, Naoko; Nishioka, Kusuki; Nakajima, Takeshi

doi:10.4161/cc.6.11.4277

Cited by 42 publications

(37 citation statements)

References 51 publications

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“…This conclusion is validated by the following observations: (i) Conditional deletion of Hrd1 specifically in B-cell lineage results in reduced mature B cells in the peripheral lymphoid organs; (ii) Hrd1-deficiency sensitizes Fas-mediated activation-induced B-cell death, which can be largely Hrd1 functions as a critical regulator in protecting B cells from AICD, based on our observation that apoptosis in Hrd1 KO peripheral B cells upon antigenic stimulation was significantly increased. Fas was up-regulated at both the mRNA and protein level, initially suggesting that Fas expression might be indirectly induced upon increase of Hrd1 substrates, such as p53 or IRE1α (27,30). However, we did not detect a significant increase in the p53-target genes PUMA and p21 in activated Hrd1 KO peripheral B cells compared with WT.…”

Section: Discussioncontrasting

confidence: 48%

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Kong¹,

Yang²,

Xu³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.Hrd1 | Fas | B cells | ubiquitination B -cell immunity involves several checkpoints, which are important to orchestrate and balance survival and apoptotic signals and control the quality and size of the B-cell compartment (1, 2). The earliest steps in B-cell development occur in the bone marrow, where assembly of the pre-B-cell receptor (pre-BCR) followed by the mature BCR occurs in distinct stages. Once the mature BCR is expressed, B lymphocytes then progress into the immature B-cell stage, where further selection checkpoints occur before the immature B cells transition to the periphery and mature into circulating B cells (2, 3). Mature B cells are maintained through tonic BCR, CD40, and B-cell-activating factor receptor (BAFFR) signaling (4). Activation by cross-linking the BCR leads to rapid proliferation, somatic hypermutation, and further differentiation of B cells (5, 6). The expansion of activated B-cell compartment is subsequently downmodulated through activation-induced cell death (AICD) (7,8).The death receptor Fas has been identified as a key regulator of AICD of B cells (9-11). Fas is highly expressed on activated B cells, particularly in the germinal center, where it mediates the deletion of autoreactive or unproductive somatic hypermutated B cells (12)(13)(14). Fas, as well as its ligand FasL, play critical roles in B-cell apoptosis. The selective removal of Fas from activated B cells results in lupus-like disease and autoantibody production (15-17). It has been a widely accepted view that the Fas/FasL mutations result in, at least in part, a failure to eliminate self-reactive GC B cells in autoimmune patients and animal models (12, 18). However, more recent studies show that FAS is in fact not required for the elimination of self-reactive GC B cells. Instead, Fas inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation and survived despite losing antigen reactivity (8). Nevertheless, it is clear that Fasmediated B-cell death is critically involved in B-cell-mediated autoimmune diseases. However, the molecular...

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Section: Discussioncontrasting

confidence: 48%

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Kong¹,

Yang²,

Xu³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Limited evidence suggests that several of them are oncogenic E3 ligases. For example, SYVN1 has been shown to target p53 and gp78 for degradation (31,32), LPXN may promote prostate cancer metastasis by serving as a co-activator of androgen receptors (33,34), and TRIM8 may promote STAT3 and NF-kB activation (35,36). These candidate E3 ligases warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation

et al. 2013

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To identify novel oncogenic E3 ubiquitin ligases as anticancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the sulphorhodamine B assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a candidate from this screening. Knockdown of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 knockdown delayed cell-cycle G 1 -S progression and decreased cell proliferation. Using protein array analysis we found that RNF126 silencing increased cell-cycle dependent kinase inhibitor p21 cip protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased p21 mRNA levels. We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in PC3 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in a subset of breast cancer cell lines and negatively correlated with p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation by targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers. Cancer Res; 73(1); 385-94. Ó2012 AACR.

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“…The inflammatory and pro-inflammatory mediators are thought to play an important role in pathologies of RA. Chronic inflammatory reactions in RA could be induced by inflammatory cytokines, including an excess of reactive oxygen species (ROS) [13], an activation of p66Shc gene which possibly regulates the levels of oxidative stress in the body, and an increase in active molecules as chaperones which induce endoplasmic reticulum (ER) stress [14]. However, an involvement of p66Shc and ER stress in adjuvant arthritis has not been evaluated yet.…”

Section: Introductionmentioning

confidence: 99%

ER Stress, P66shc, and P-Akt/Akt Mediate Adjuvant-Induced Inflammation, Which Is Blunted by Argirein, a Supermolecule and Rhein in Rats

et al. 2011

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We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.

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The Roles of Synoviolin in Crosstalk Between Endoplasmic Reticulum Stress-Induced Apoptosis and p53 Pathway

Cited by 42 publications

References 51 publications

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation

ER Stress, P66shc, and P-Akt/Akt Mediate Adjuvant-Induced Inflammation, Which Is Blunted by Argirein, a Supermolecule and Rhein in Rats

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