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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
NF-κB transcriptionally regulates expression of genes which are involved in cell survival, apoptosis, differentiation and immune responses [42, 43]. As discussed above, NF-κB family consists of five members. Both the precursors (NF-κB1/p105 and NF-κB2/ p100) contain IκB-homologous regions at the C-terminal that function as NF-κB inhibitors. Proteolytic processing removes inhibitory domains, allowing the processed proteins (NF-κB1/ p50 and NF-κB2/p52) to enter into the nucleus. Inside the nucleus, p50 and p52 form homodimers or heterodimers with Rel family proteins [42]. All these NF-κB associated proteins have Rel homology domain (RHD) at the N-terminal region. Some of the NF-κB proteins (p65, c-Rel and RelB) contain transcriptional activation domain (TAD) at C-terminal, and these TAD containing proteins positively regulate transcriptional activity. On the other hand, two TAD lacking proteins, p52 and p100, negatively regulate gene expression when bound as homodimer, but can activate gene expression when recruited with other TAD containing proteins like p65. RelB and cRel [44]. Activation of NF-κB pathway is either by classical/canonical or the alternate/non-canonical signaling pathways.
The Genetic Basis of NEC Susceptibility
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Lovya George, Wei Yu, Alain Cuna, Venkatesh Sampath
NFKB is a pluripotent transcription factor that upon activation by TLRs and other inflammatory cascades regulates the expression of genes involved in inflammation, cell cycle, and reparative responses (37). NFKB levels are increased in the intestinal mucosa following NEC induction in rats, and inhibiting NFKB protects against excessive inflammation and decreases mortality (38, 39). Sampath et al. (16) found that the NFKB1 (g.-24519delATTG) variant was present in all 15 infants with NEC compared to only 166 of 256 controls (100% vs. 65%, p = 0.003), suggesting that this variant may be necessary, but not sufficient, for causing NEC. On the other hand, NFKBIA (g.1004A>G) variant was less common in infants with NEC, suggesting that this variant may confer protection against NEC. While this suggests a potential role for NFKB variants in NEC, considering its pleiotropic role, it may confer increased or decreased risk.
Nutraceutical’s Role in Proliferation and Prevention of Gynecological Cancers
Published in Sheeba Varghese Gupta, Yashwant V. Pathak, Advances in Nutraceutical Applications in Cancer, 2019
Aaishwarya B. Deshmukh, Jayvadan K. Patel, Bharat Mishra
NF-κB as a nuclear factor was found to bind to the enhancer element of the immunoglobulin kappa light chain of activated B cells (hence abbreviated NF-κB) [41]. The five members of NF-κB group of proteins identified are RelB, p65 (RelA), NF-κB1 (p105/p50), NF-κB2 (p100/p52), and c-Rel [42–45]. The expression of genes involved in the various processes of transformation and development of tumor cells is regulated by the transcription factor NF-κB by various proinflammatory stimuli such as TNF-α, lipopolysaccharide, IL-1b, and oxidative stress, which induce expression of multiple genes encoding proinflammatory cytokines, growth and angiogenic factors, chemokines adhesion molecules, such as ICAM-1 and e-selectin VCAM-1, and inducible enzymes like iNOS and COX-2 [46]. The apprehension that the c-rel, which is a cellular homologue of the oncogene v-rel, encodes for a NF-κB subunit and binds to the same DNA binding domain has given the first proof of link between NF-κB and cancer [47]. In addition, the detection of active NF-κB in cancer tissues of the patients, including those with lymphoma and leukemia and cancers of breast, prostate, pancreas, oral cavity, colon, liver, and ovary support the link between NF-κB and cancer [48]. All these point to the relevance or importance of NF-κB pathway in cancer, and so this pathway has been manifested as a favored target for therapeutic development.
Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection
Published in Renal Failure, 2022
Long He, Boqian Wang, Xueyi Wang, Yuewen Liu, Xing Song, Yijian Zhang, Xin Li, Hongwei Yang
Based on regulatory networks between miRNAs and PTPRC, CD8A, CD86, ITGAM, and CCR5, three miRNA-key gene regulatory pairs were identified, including hsa-miR-8485-ITGAM/CD86, hsa-miR-12123-PTPRC, and hsa-miR-664a-3p-CCR5/CD8A. In addition, TFs of NFKB1 and RELA regulated the expression of CCR5 and CD86. NFKB1 is an inflammatory marker. After kidney transplantation, the NFKB1 promoter polymorphism (-94ins/delATTG) is related to susceptibility to cytomegalovirus infection [85]. Increased expression of RELA is associated with renal thrombotic microangiopathy [86]. Our result suggested that the regulation relationship between miRNA, TFs and PTPRC, CD8A, CD86, ITGAM, and CCR5 could be associated with inflammatory response in the development of allograft rejection after the kidney transplant.
Variations in Toll-like receptor and nuclear factor-kappa B genes and the risk of glioma
Published in British Journal of Neurosurgery, 2019
Idris Kına, Gonul Kanigur Sultuybek, Tugba Soydas, Guven Yenmis, Huseyin Biceroglu, Ahmet Dirican, Mustafa Uzan, Turgut Ulutin
Several studies support the concept that many types of malignancies, including glioblastoma, have strong associations with NF-KB pathways. A widely discussed NFKB1 polymorphism is the -94 insertion/deletion ATTG (rs28362491). This causes a modification in the promoter region of the NFKB1 gene between two important regulatory elements: activator protein 1 and KB binding site. This alters mRNA stability and hence translation efficiency via reducing or preventing the binding to nuclear proteins and yields to lower transcript levels of the NFKB1 gene.30,31 As this modification is proximal to binding sites that are important for promoter regulation, the ATTG deletion allele leads to very reduced promoter activity and is involved in lower levels of p50 protein expression. Therefore, different levels of the protein subunits between carriers of the -94ins allele and the -94del allele may be expected to contribute to variations in cancer risk. Using a reporter assay, a previous study reported that the -94ins/del ATTG polymorphism has a regulatory effect on NFKB1 gene expression and that the activity of the ins allele is higher than del allele by 2 fold.30
Gene expression changes in rat brain regions after 7- and 28 days inhalation exposure to exhaust emissions from 1st and 2nd generation biodiesel fuels - The FuelHealth project
Published in Inhalation Toxicology, 2018
Renate Valand, Pål Magnusson, Katarzyna Dziendzikowska, Malgorzata Gajewska, Jacek Wilczak, Michał Oczkowski, Dariusz Kamola, Tomasz Królikowski, Marcin Kruszewski, Anna Lankoff, Remigiusz Mruk, Dag Marcus Eide, Rafał Sapierzyński, Joanna Gromadzka-Ostrowska, Nur Duale, Johan Øvrevik, Oddvar Myhre
DEE from B7 elicits statistically significant increase in the expression of Il18 and Nfkb1 in the frontal cortex. Further, Tnf was statistically significantly lowered only for B20. DEP is shown to impair the blood-brain barrier and cause capillaries to release TNF-α in vitro, contributing to inflammation (Hartz et al., 2008). Our results indicate that different blends of biodiesel can influence the expression of Nfκb1 differently. The NFKB1 subunits p105/p50 are important regulators of NF-KB activity in vivo. The importance of Nfkb1 function can be seen in mouse models, where Nfkb1 knockout mice display increased inflammation and susceptibility to certain forms of DNA damage (Cartwright et al., 2016). In an experimental study, mice were exposed to different size PM from traffic-polluted areas (MohanKumar et al., 2008). They found conflicting results on the activation of NF-κB and suggested that the differences were due to different PM composition and mass. Since PAHs can activate NF-κB activity (Volkov & Kobliakov, 2011), it is likely that B7 exposure increases the NFκB1 expression due to the higher PAH content.