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      IκB-α: At the crossroad between oncogenic and tumor-suppressive signals

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          Abstract

          Nuclear factor κB (NF-κB) is an essential component of tumorigenesis and resistance to cancer treatments. NFKB inhibitor α (IκB-α) acts as a negative regulator of the classical NF-κB pathway through its ability to maintain the presence of NF-κB in the cytoplasm. However, IκB-α is also able to form a complex with tumor protein p53, promoting its inactivation. Recently, we demonstrated that IκB-α is able to mediate p53 nuclear exclusion and inactivation in chronic myeloid leukemia, indicating that IκB-α can modulate either oncogenic or tumor-suppressive functions, with important implications for cancer treatment. The present review describes the role of IκB-α in cancer pathogenesis, with particular attention to hematological cancers, and highlights the involvement of IκB-α in the regulation of p53 tumor-suppressive functions.

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          Most cited references36

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          Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation.

          Nuclear factor-kappaB (NF-kappaB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Activation of NF-kappaB mainly occurs via IkappaB kinase (IKK)-mediated phosphorylation of inhibitory molecules, including IkappaBalpha. Optimal induction of NF-kappaB target genes also requires phosphorylation of NF-kappaB proteins, such as p65, within their transactivation domain by a variety of kinases in response to distinct stimuli. Whether, and how, phosphorylation modulates the function of other NF-kappaB and IkappaB proteins, such as B-cell lymphoma 3, remains unclear. The identification and characterization of all the kinases known to phosphorylate NF-kappaB and IkappaB proteins are described here. Because deregulation of NF-kappaB and IkappaB phosphorylations is a hallmark of chronic inflammatory diseases and cancer, newly designed drugs targeting these constitutively activated signalling pathways represent promising therapeutic tools.
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            Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

            Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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              How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex.

              M Karin (1999)
              Rel/NF-kappaB transcription factors are primarily regulated by association with inhibitor IkappaB proteins. Thus, in most cells NF-kappaB exists in the cytoplasm in an inactive complex bound to IkappaB. Most agents that activate NF-kappaB do so through a common pathway based on phosphorylation-induced, proteasome-mediated degradation of IkappaB. The key regulatory step in this pathway involves activation of a high molecular weight IkappaB kinase (IKK) complex, whose catalysis is generally carried out by a heterodimeric kinase consisting of IKKalpha and IKKbeta subunits. This review describes the identification of proteins in the IKK complex, and the regulation and physiological functions of IKK.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                February 2017
                06 December 2016
                06 December 2016
                : 13
                : 2
                : 531-534
                Affiliations
                Department of Clinical and Biological Sciences, University of Turin, I-10043 Orbassano, Turin, Italy
                Author notes
                Correspondence to: Dr Alessandro Morotti, Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, I-10043 Orbassano, Turin, Italy, E-mail: alessandro.morotti@ 123456unito.it
                Article
                OL-0-0-5465
                10.3892/ol.2016.5465
                5351326
                761888af-ea91-43c0-9172-501a50e11b4b
                Copyright: © Morotti et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 23 November 2015
                : 19 August 2016
                Categories
                Review

                Oncology & Radiotherapy
                iκb-α,nfkb inhibitor α,chronic myeloid leukemia,nf-κb,p53
                Oncology & Radiotherapy
                iκb-α, nfkb inhibitor α, chronic myeloid leukemia, nf-κb, p53

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