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      The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases

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          Abstract

          The nuclear factor kappa B (NF-kB) family of transcription factors plays an essential role as stressors in the cellular environment, and controls the expression of important regulatory genes such as immunity, inflammation, death, and cell proliferation. NF-kB protein is located in the cytoplasm, and can be activated by various cellular stimuli. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex molecular interactions with adapter proteins and phosphorylation and ubiquitinase enzymes. Accordingly, this increases NF-kB translocation in the nucleus and regulates gene expression. In this study, the concepts that emerge in different cellular systems allow the design of NF-kB function in humans. This would not only allow the development for rare diseases associated with NF-kB, but would also be used as a source of useful information to eliminate widespread consequences such as cancer or inflammatory/immune diseases.

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          Most cited references107

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          Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

          Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
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            Shared principles in NF-kappaB signaling.

            The transcription factor NF-kappaB has served as a standard for inducible transcription factors for more than 20 years. The numerous stimuli that activate NF-kappaB, and the large number of genes regulated by NF-kappaB, ensure that this transcription factor is still the subject of intense research. Here, we attempt to synthesize some of the basic principles that have emerged from studies of NF-kappaB, and we aim to generate a more unified view of NF-kappaB regulation.
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              Points of control in inflammation.

              Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                18 July 2020
                May 2021
                18 July 2020
                : 8
                : 3
                : 287-297
                Affiliations
                [a ]Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, 1336616357, Iran
                [b ]Centre for Experimental Medicine, Queen's University Belfast, Belfast, BT7 1NN, United Kingdom
                [c ]Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, 1336616357, Iran
                [d ]Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, 1336616357, Iran
                [e ]Department of Medical Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1336616357, Iran
                Author notes
                []Corresponding author. zinati3333@ 123456gmail.com
                [∗∗ ]Corresponding author. srmiri@ 123456sina.tums.ac.ir
                [†]

                These authors contributed equally to this study.

                Article
                S2352-3042(20)30077-5
                10.1016/j.gendis.2020.06.005
                8093649
                33997176
                be736008-e537-4238-98d0-01be4ddb9bce
                © 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 November 2019
                : 26 May 2020
                : 12 June 2020
                Categories
                Review Article

                cancer,immunity,inflammation,nf-κb,signaling
                cancer, immunity, inflammation, nf-κb, signaling

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