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IL-1 specifically triggers casein kinase II-mediated p65 phosphorylation in EMT-6J cells. A, time course of IL-1-induced p65 phosphorylation in indicated cell clones exposed to 0.55 ng/ml IL-1 for indicated times. Upper panel, serine-phosphorylated proteins were immunoprecipitated, and the presence of p65 in the immunocomplexes was detected by Western blotting. Lower panel, Western blot analysis of p65 expression. B, EMT-6J cells were exposed to indicated kinase inhibitors (H89, 20 M; DRB, 30 M; LY-294002, 25 M) for 1 h, then treated for 20 min with 0.55 ng/ml IL-1. Upper panel, immunoprecipitation of serine-phosphorylated proteins and detection of p65 by Western blot. Lower panel, Western blot analysis of p65 expression. C, EMT-6J cells were treated for 1 h with 30 M DRB, then stimulated for 30 min with 0.55 ng/ml IL-1 before Western blot analysis of indicated proteins. Loading control, HSC70. D, the indicated cells were co-transfected with an NF-B-dependent-luciferase reporter gene p(NF-B) 4-luc and either a siRNA control or a CKII-subunit-specific siRNA before stimulation with 0.55 ng/ml IL-1 for 15 h. Activity:-fold induction relative to control non-stimulated cells transfected with a control siRNA. *, n 3, p 0.05 versus EMT-6J cells co-transfected with a control siRNA and exposed to IL-1.
Source publication
Nitric oxide (NO) produced by inducible nitric-oxide synthase (NOSII) is mainly regulated at the transcriptional level by the nuclear factor-kappaB (NF-kappaB). In the present study, we further analyzed the role of NF-kappaB in the in vivo transcriptional regulation of NOSII gene by comparing two clones isolated from the EMT-6 mouse mammary cancer...
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Citations
... Studies have shown that the stimulation of macrophage IL-1 receptors by IL-1β produced by PDAC cells could lead to the activation of Casein Kinase I and II in macrophages, which in turn phosphorylated the p65 subunit of NF-κB heterodimer, resulting in the increased activation of NF-κB. 47 The activated NF-κB might then trans-locate into the nucleus and stimulate the transcription of the mRNA of inflammatory components, such as pro-IL-1β, TNF-α, the NLRP3 inflammasome, and other inflammasomes (Figures 6, 7). 48 The expressed cytokines could further contribute to the tumor microenvironment between macrophages and PDAC cells by repressing PP2A in PDAC cells. ...
Modified macrophages, tumor-associated macrophages (TAMs), are key contributors to the survival, growth, and metastatic behavior of pancreatic ductal adenocarcinoma (PDAC) cells. Central to the role of inflammation and TAMs lies the NLRP3 inflammasome. This study investigated the effects of LPS-stimulated inflammation on cell proliferation, levels of pro-inflammatory cytokines, and the NLRP3 inflammasome pathway in a co-culture model using PDAC cells and macrophages in the presence or absence of MCC950, a NLRP3-specific inhibitor. The effects of LPS-stimulated inflammation were tested on two PDAC cell lines (Panc 10.05 and SW 1990) co-cultured with RAW 264.7 macrophages. Cell proliferation was determined using the MTT assay. Levels of pro-inflammatory cytokines, IL-1β, and TNF-α were determined by ELISA. Western blot analyses were used to examine the expression of NLRP3 in both PDAC cells and macrophages. The co-culture and interaction between PDAC cell lines and macrophages led to pro-inflammatory microenvironment under LPS stimulation as evidenced by high levels of secreted IL-1β and TNF-α. Inhibition of the NLRP3 inflammasome by MCC950 counteracted the effects of LPS stimulation on the regulation of the NLRP3 inflammasome and pro-inflammatory cytokines in PDAC and macrophages. However, MCC950 differentially modified the viability of the metastatic vs primary PDAC cell lines. LPS stimulation increased PDAC cell viability by regulating the NLRP3 inflammasome and pro-inflammatory cytokines in the tumor microenvironment of PDAC cells/macrophages co-cultures. The specific inhibition of the NLRP inflammasome by MCC950 effectively counteracted the LPS-stimulated inflammation.
... For the immortalization of EBV-infected cells, LMP1 activates RelAp65 to bind to the human telomerase reverse transcriptase (hTERT) to activate telomerase and thereby induce EBVmediated immortalization. It has been known for quite some time that CK2 regulates the NF-κB pathway through the phosphorylation of several components of this pathway, such as RelAp65, IκB, IKK2 and NF-κB [143][144][145][146][147] (Figure 1). In the nucleus, CK2 binds to and phosphorylates RelAp65 at serine 529 [148]. ...
Protein kinase CK2 is a pleiotropic protein kinase, which phosphorylates a number of cellular and viral proteins. Thereby, this kinase is implicated in the regulation of cellular signaling, controlling of cell proliferation, apoptosis, angiogenesis, immune response, migration and invasion. In general, viruses use host signaling mechanisms for the replication of their genome as well as for cell transformation leading to cancer. Therefore, it is not surprising that CK2 also plays a role in controlling viral infection and the generation of cancer cells. Epstein–Barr virus (EBV) lytically infects epithelial cells of the oropharynx and B cells. These latently infected B cells subsequently become resting memory B cells when passing the germinal center. Importantly, EBV is responsible for the generation of tumors such as Burkitt’s lymphoma. EBV was one of the first human viruses, which was connected to CK2 in the early nineties of the last century. The present review shows that protein kinase CK2 phosphorylates EBV encoded proteins as well as cellular proteins, which are implicated in the lytic and persistent infection and in EBV-induced neoplastic transformation. EBV-encoded and CK2-phosphorylated proteins together with CK2-phosphorylated cellular signaling proteins have the potential to provide efficient virus replication and cell transformation. Since there are powerful inhibitors known for CK2 kinase activity, CK2 might become an attractive target for the inhibition of EBV replication and cell transformation.
... Inhibition of the kinase activity of CK2 identified CK2 as a negative regulator of USF1 regulated transcription of PDX1 [21]. NF-κB is also a substrate for CK2 [54][55][56][57]. siRNA induced down-regulation of CK2 decreases NF-κB nuclear localization, DNA binding and transcriptional activity [58]. ...
Glucose homeostasis is of critical importance for the survival of organisms. It is under hormonal control and often coordinated by the action of kinases and phosphatases. We have previously shown that CK2 regulates insulin production and secretion in pancreatic β-cells. In order to shed more light on the CK2-regulated network of glucose homeostasis, in the present study, a qRT-PCR array was carried out with 84 diabetes-associated genes. After inhibition of CK2, fructose-1,6-bisphosphatase 1 (FBP1) showed a significant lower gene expression. Moreover, FBP1 activity was down-regulated. Being a central enzyme of gluconeogenesis, the secretion of glucose was decreased as well. Thus, FBP1 is a new factor in the CK2-regulated network implicated in carbohydrate metabolism control.
... At 12hrpf, our results show that regulatory kinase activity includes phosphorylation by CSNK2A1 and CSNK2A2 (Fig. 3e-f ), two key subunits of CK2, a pleiotropic protein kinase that functions in many signaling networks, including Wnt and the PI3K/AKT/PTEN axis [38]. CK2 promotes survival through enhanced NF-κB activity to regulate the inflammatory response [39,40], thus activating transcription of both IL-6 [41] and IL-8 [42], which are activated in the boa intestine ( Fig. 3a-b). IL-8 Signaling is a central regulator with high overlap in expressed pathways at 1dpf and 3dpf (Fig. 2d), and both IL-8 and IL-6 signaling pathways are significantly active throughout the time series (Figs. ...
... In the boa, after the immediate oxidative and ER stress response, our results newly implicate the activation of a CK2/NF-κB/IL-6/IL-8 axis that controls inflammation and proliferation to support intestinal regeneration and the shift from stress response to growth. CK2 promotes cell survival through increased NF-κB activity to regulate the inflammatory response [39,40]. This is further supported by the activation of two important NF-κB targets, IL-6 [41] and IL-8 [42], in the boa intestine, both of which promote inflammation, proliferation, and regeneration [61,62]. ...
Background
Snakes exhibit extreme intestinal regeneration following months-long fasts that involves unparalleled increases in metabolism, function, and tissue growth, but the specific molecular control of this process is unknown. Understanding the mechanisms that coordinate these regenerative phenotypes provides valuable opportunities to understand critical pathways that may control vertebrate regeneration and novel perspectives on vertebrate regenerative capacities.
Results
Here, we integrate a comprehensive set of phenotypic, transcriptomic, proteomic, and phosphoproteomic data from boa constrictors to identify the mechanisms that orchestrate shifts in metabolism, nutrient uptake, and cellular stress to direct phases of the regenerative response. We identify specific temporal patterns of metabolic, stress response, and growth pathway activation that direct regeneration and provide evidence for multiple key central regulatory molecules kinases that integrate these signals, including major conserved pathways like mTOR signaling and the unfolded protein response.
Conclusion
Collectively, our results identify a novel switch-like role of stress responses in intestinal regeneration that forms a primary regulatory hub facilitating organ regeneration and could point to potential pathways to understand regenerative capacity in vertebrates.
... Treating MCF-7 breast cancer cells with ectopic oxoDNA resulted in increased levels of nuclear p65 NFjB proteins phosphorylated at Ser529 (Kostyuk et al., 2013). This phosphorylation increases NFjB transactivation (Chantôme et al., 2004;Jaksch & Thams, 2014;Wang, Westerheide, Hanson, & Baldwin, 2000), and activated p65 NFjB induce BACE1 (Chami et al., 2012;Chen et al., 2012). This suggests that oxoDNA might augment BACE1 transcription in part via CK2 and NFjB activation in AD patients' brains (Buchhave et al., 2010;Cheng et al., 2014;Deng, Zhang, Liu, Chen, & Yu, 2017;Kostyuk et al., 2013;Wang et al., 2006;Yamamoto et al., 2007). ...
In Alzheimer’s disease (AD), amyloid-β (Aβ) generation and upstream β-secretase 1 (BACE1) expression appear to be driven by oxidative stress via c-Jun N-terminal kinase (JNK), p38, and Interferon-Induced, Double-Stranded RNA-Activated Protein Kinase (PKR). In addition, inflammatory molecules, including lipopolysaccharide (LPS), induce genes central to Aβ genesis, such as BACE1, via nuclear factor-κB (NFκB). However, additional triggers of Aβ generation remain poorly understood and might represent novel opportunities for therapeutic intervention. Based on mechanistic studies and elevated ectopic oxidatively damaged DNA (oxoDNA) levels in preclinical AD, mild cognitive impairment, and AD patients, we hypothesize oxoDNA contributes to β-amyloidosis starting from the earliest stages of AD through multiple pathways. OxoDNA induces mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 transcription. It also induces myeloid differentiation primary response 88 (MyD88) and activates protein kinase CK2, thereby increasing NFκB activation and BACE1 induction. OxoDNA increases oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) ectopic localization, likely augmenting JNK-mediated BACE1 induction. OxoDNA likely also promotes β-amyloidosis via absent in melanoma 2 (AIM2) induction. Falsifiable predictions of this hypothesis include that deoxyribonuclease treatment should decrease Aβ and possibly slow cognitive decline in AD patients. While formal testing of this hypothesis remains to be performed, a case report has found deoxyribonuclease I treatment improved a severely demented AD patient’s Mini-Mental Status Exam score from 3 to 18 at 2 months. There is preliminary preclinical and clinical evidence suggesting that ectopic oxidatively damaged DNA may act as an inflammatory damage-associated molecular pattern contributing to Aβ generation in AD, and deoxyribonuclease I should be formally evaluated to test whether it can decrease Aβ levels and slow cognitive decline in AD patients.
... Furthermore, higher expression of CSNK2A1 is associated with shorter survival in patients with breast cancer [10], clear cell renal cell carcinoma [8], and gastric cancer [5]. CSNK2A1 is involved in cancer progression by regulating various cancer-promoting signaling pathways, such as the MYC, PI3K-Akt, NFκB, and Wnt/β-catenin pathways [3,[10][11][12][13][14]. These biological roles of CSNK2A1 in cancer are closely related to its kinase activity on the targets involved in tumorigenesis [5,10]. ...
... The molecular mechanisms and roles of CSNK2A1 in tumorigenesis have been extensively investigated, and it has been shown that CSNK2A1 is involved in tumorigenesis by its roles as a kinase to activate oncogenic molecules and to stimulate degradation of tumor suppressors [3,12,40,41]. Consequently, CSNK2A1 promotes the proliferation and invasiveness of cancer cells by activating cell-cycle progression and the epithelial-to-mesenchymal transition (EMT) [4,5,10,13]. CSNK2A1 engages the MYC [11], Akt [13,14], and NFκB [12] pathways to stimulate the proliferation of cancer cells. ...
... Consequently, CSNK2A1 promotes the proliferation and invasiveness of cancer cells by activating cell-cycle progression and the epithelial-to-mesenchymal transition (EMT) [4,5,10,13]. CSNK2A1 engages the MYC [11], Akt [13,14], and NFκB [12] pathways to stimulate the proliferation of cancer cells. In myeloid neoplasms, the depletion of CSNK2A1 inhibited cell-cycle progression by elevating P27 [42]. ...
CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.
... renal cell carcinoma [8], and gastric cancer [5]. CSNK2A1 is involved in cancer progression by regulating various cancer-promoting signaling pathways such as MYC, PI3K-Akt, NFκB, and Wnt/β-catenin pathways [3,[10][11][12][13][14]. These biological roles of CSNK2A1 in cancer are closely related to its kinase activity on the targets involved in tumorigenesis [5,10]. ...
... The molecular mechanisms and roles of CSNK2A1 in tumorigenesis were extensively investigated, and it has been shown that CSNK2A1 is involved in tumorigenesis by its roles as a kinase to activate oncogenic molecules and to stimulate degradation of tumor suppressors [3,12,40,41]. Consequently, CSNK2A1 ...
... promotes the proliferation and invasiveness of cancer cells by activating cell cycle progression and the epithelial-to-mesenchymal transition (EMT) [4,5,10,13]. CSNK2A1 engages the MYC [11], Akt [13,14], and NFκB [12] pathways to stimulate the proliferation of cancer cells. In myeloid neoplasm, depletion of CSNK2A1inhibited cell cycle progression by elevating P27 [42]. ...
Background
CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to the conventional anti-cancer therapies.
Methods
We evaluated the expression of CSNK2A1 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and phosphorylation of SIRT6 on Ser338 on the resistance to the anti-cancer effects of doxorubicin.
Results
Higher expression of CSNK2A1 predicted shorter overall survival and relapse-free survival in both general osteosarcoma patients and sub-population of patients who received postoperative chemotherapies. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to cytotoxic effects of doxorubicin, and knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and induction of the DNA damage repair pathway molecules ATM and Chk2. CSNK2A1 and SIRT6 mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells in vitro.
Conclusions
This study demonstrates that the expression of CSNK2A1 might be used as a prognostic indicator of osteosarcoma. In addition, it suggests that CSNK2A1 induces resistance to doxorubicin through phosphorylation of SIRT6-mediated activation of the DNA damage repair pathway. Therefore, blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for the poor prognostic subgroup of osteosarcomas with high expression of CSNK2A1.
... Collectively, we conclude that CK2 functions as a negative regulator of NF-κB in senescent cells. This is not consistent with previous reports that CK2 induces NF-κB activation at multiple levels through IκB [30], inducible IKK and IKKε [31], IKK2 [32], or RelA/p65 itself [33,34]. Although we currently cannot explain this discrepancy, we hypothesize that CK2 may regulates NF-κB activity by different mechanisms depending on the state of cell growth (e.g., proliferation or senescence). ...
Senescent cells secrete pro-inflammatory factors, and a hallmark feature of senescence is senescence-associated secretory phenotype (SASP). The aim of this study is to investigate the protein kinase CK2 (CK2) effects on SASP factors expression in cellular senescence and organism aging. Here CK2 down-regulation induced the expression of SASP factors, including interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 3, through the activation of nuclear factor-κB (NF-κB) signaling in MCF-7 and HCT116 cells. CK2 down-regulation-mediated SIRT1 inactivation promoted the degradation of inhibitors of NF-κB (IκB) by activating the AKT-IκB kinase (IKK) axis and increased the acetylation of lysine 310 on RelA/p65, an important site for the activity of NF-κB. kin-10 (the ortholog of CK2β) knockdown increased zmp-1, -2, and -3 (the orthologs of MMP) expression in nematodes, but AKT inhibitor triciribine and SIRT activator resveratrol significantly abrogated the increased expression of these genes. Finally, antisense inhibitors of miR-186, miR-216b, miR-337-3p, and miR-760 suppressed CK2α down-regulation, activation of the AKT-IKK-NF-κB axis, RelA/p65 acetylation, and expression of SASP genes in cells treated with lipopolysaccharide. Therefore, this study indicated that CK2 down-regulation induces the expression of SASP factors through NF-κB activation, which is mediated by both activation of the SIRT1-AKT-IKK axis and RelA/p65 acetylation, suggesting that the mixture of the four miRNA inhibitors can be used as anti-inflammatory agents.
... In addition, CK2 activity results in the activation of NF-jB via its ability to phosphorylate the p65 subunit of the NF-jB dimer in response to IL-1 in hepatocytes as well as in fibroblasts [53] and controls TNF-a dependent phosphorylation of p65 [54]. CK2 phosphorylation and activation of NF-jB is also involved in NF-jB transcription of iNOS in response to IL-1 and LPS [55]. In intestinal epithelial cells, IL-1 stimulation leads to enhanced activation of CK2 bound to IKK or the p65 subunit of the NF-jB and inhibition of CK2 activity attenuated the expression of NF-jB-transcribed proinflammatory factors [56]. ...
Protein kinase CK2, formally known as casein kinase II, is ubiquitously expressed and highly conserved serine/threonine or tyrosine kinase enzyme that regulates diverse signaling pathways responsible for cellular processes (i.e., cell proliferation and apoptosis) via interactions with over 500 known substrates. The enzyme’s physiological interactions and cellular functions have been widely studied, most notably in the blood and solid malignancies. CK2 has intrinsic role in carcinogenesis as overexpression of CK2 subunits (α, α`, and β) and deregulation of its activity have been linked to various forms of cancers. CK2 also has extrinsic role in cancer stroma or in the tumor microenvironment (TME) including the immune cells. However, very few research studies have focused on extrinsic role of CK2 in regulating immune responses as a therapeutic alternative for cancer. The following review discusses CK2’s regulation of key signaling events [Nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activators of transcription (JAK/STAT), Hypoxia inducible factor–1alpha (HIF-1α), Cyclooygenase-2 (COX-2), Extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), Notch, Protein kinase B/AKT, Ikaros and Wnt] that can influence the development and function of immune cells in cancer. Potential clinical trials using potent CK2 inhibitors will facilitate and improve the treatment of human malignancies.
... Previous studies have shown that CK2 can mediate the activation of NF-kB induced by serum factors via phosphorylating the IKK complex and promoting IkBa (a NF-kB endogenous inhibitor) degradation and releasing p65 Ser536/p50 [17]. Moreover, CK2 induced phosphorylation of IkBa at Ser-283, Ser-289, Ser-293, and Thr-291, as well as phosphorylation of p65 at Ser529 to activate NF-kB directly [38,43]. Therefore, CK2 subunits are critical to controlling trans-activation of NF-kB. ...
Background:
Tumor necrosis factor α-induced protein 1 (TNFAIP1) is frequently downregulated in cancer cell lines and promotes cancer cell apoptosis. However, its role, clinical significance and molecular mechanisms in hepatocellular carcinoma (HCC) are unknown.
Methods:
The expression of TNFAIP1 in HCC tumor tissues and cell lines was measured by Western blot and immunohistochemistry. The effects of TNFAIP1 on HCC proliferation, apoptosis, metastasis, angiogenesis and tumor formation were evaluated by Cell Counting Kit-8 (CCK8), Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL), transwell, tube formation assay in vitro and nude mice experiments in vivo. The interaction between TNFAIP1 and CSNK2B was validated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), Co-immunoprecipitation and Western blot. The mechanism of how TNFAIP1 regulated nuclear factor-kappaB (NF-κB) pathway was analyzed by dual-luciferase reporter, immunofluorescence, quantitative Real-time polymerase chain reaction (RT-qPCR) and Western blot.
Findings:
The TNFAIP1 expression is significantly decreased in HCC tissues and cell lines, and negatively correlated with the increased HCC histological grade. Overexpression of TNFAIP1 inhibits HCC cell proliferation, metastasis, angiogenesis and promotes cancer cell apoptosis both in vitro and in vivo, whereas the knockdown of TNFAIP1 in HCC cell displays opposite effects. Mechanistically, TNFAIP1 interacts with CSNK2B and promotes its ubiquitin-mediated degradation with Cul3, causing attenuation of CSNK2B-dependent NF-κB trans-activation in HCC cell. Moreover, the enforced expression of CSNK2B counteracts the inhibitory effects of TNFAIP1 on HCC cell proliferation, migration, and angiogenesis in vitro and in vivo.
Interpretation:
Our results support that TNFAIP1 can act as a tumor suppressor of HCC by modulating TNFAIP1/CSNK2B/NF-κB pathway, implying that TNFAIP1 may represent a potential marker and a promising therapeutic target for HCC.
