Noncanonical NF-κB in Cancer

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2018 Jun 8

PMID 29874793

Citations 36

Authors

Matthew Tegowski

Albert Baldwin

Affiliations

Soon will be listed here.

Abstract

The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Here, we review noncanonical NF-κB pathways and discuss its important roles in promoting cancer. We also discuss alternative NF-κB-independent functions of some the components of noncanonical NF-κB signaling. Finally, we discuss important crosstalk between canonical and noncanonical signaling, which blurs the two pathways, indicating that understanding the full picture of NF-κB regulation is critical to deciphering how this broad pathway promotes oncogenesis.

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References

Brown K, Hostager B, Bishop G . Differential signaling and tumor necrosis factor receptor-associated factor (TRAF) degradation mediated by CD40 and the Epstein-Barr virus oncoprotein latent membrane protein 1 (LMP1). J Exp Med. 2001; 193(8):943-54. PMC: 2193407. DOI: 10.1084/jem.193.8.943. View

Basak S, Kim H, Kearns J, Tergaonkar V, ODea E, Werner S . A fourth IkappaB protein within the NF-kappaB signaling module. Cell. 2007; 128(2):369-81. PMC: 1831796. DOI: 10.1016/j.cell.2006.12.033. View

Authier H, Billot K, Derudder E, Bordereaux D, Riviere P, Rodrigues-Ferreira S . IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors. Proc Natl Acad Sci U S A. 2014; 111(41):14794-9. PMC: 4205659. DOI: 10.1073/pnas.1410124111. View

Xu J, Wang Y, Hua X, Xu J, Tian Z, Jin H . Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100). Oncotarget. 2016; 7(23):34112-30. PMC: 5085141. DOI: 10.18632/oncotarget.8746. View

Wang X, Belguise K, Kersual N, Kirsch K, Mineva N, Galtier F . Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol. 2007; 9(4):470-8. PMC: 2394707. DOI: 10.1038/ncb1559. View

Lawrence C, Baldwin A . Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer. PLoS One. 2016; 11(10):e0165005. PMC: 5072726. DOI: 10.1371/journal.pone.0165005. View

Guzman M, Neering S, Upchurch D, Grimes B, Howard D, Rizzieri D . Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001; 98(8):2301-7. DOI: 10.1182/blood.v98.8.2301. View

Bren G, Solan N, Miyoshi H, Pennington K, Pobst L, Paya C . Transcription of the RelB gene is regulated by NF-kappaB. Oncogene. 2001; 20(53):7722-33. DOI: 10.1038/sj.onc.1204868. View

Shih V, Davis-Turak J, Macal M, Huang J, Ponomarenko J, Kearns J . Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways. Nat Immunol. 2012; 13(12):1162-70. PMC: 3634611. DOI: 10.1038/ni.2446. View

10.

Hoffmann A, Natoli G, Ghosh G . Transcriptional regulation via the NF-kappaB signaling module. Oncogene. 2006; 25(51):6706-16. DOI: 10.1038/sj.onc.1209933. View

11.

Croucher P, Shipman C, Lippitt J, Perry M, Asosingh K, Hijzen A . Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood. 2001; 98(13):3534-40. DOI: 10.1182/blood.v98.13.3534. View

12.

Yamazaki S, Muta T, Matsuo S, Takeshige K . Stimulus-specific induction of a novel nuclear factor-kappaB regulator, IkappaB-zeta, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization. J Biol Chem. 2004; 280(2):1678-87. DOI: 10.1074/jbc.M409983200. View

13.

Cao Y, Bonizzi G, Seagroves T, Greten F, Johnson R, SCHMIDT E . IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell. 2001; 107(6):763-75. DOI: 10.1016/s0092-8674(01)00599-2. View

14.

Claudio E, Brown K, Park S, Wang H, Siebenlist U . BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol. 2002; 3(10):958-65. DOI: 10.1038/ni842. View

15.

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

16.

Xiao G, Fong A, Sun S . Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J Biol Chem. 2004; 279(29):30099-105. DOI: 10.1074/jbc.M401428200. View

17.

Maier H, Marienfeld R, Wirth T, Baumann B . Critical role of RelB serine 368 for dimerization and p100 stabilization. J Biol Chem. 2003; 278(40):39242-50. DOI: 10.1074/jbc.M301521200. View

18.

Jacque E, Tchenio T, Piton G, Romeo P, Baud V . RelA repression of RelB activity induces selective gene activation downstream of TNF receptors. Proc Natl Acad Sci U S A. 2005; 102(41):14635-40. PMC: 1253600. DOI: 10.1073/pnas.0507342102. View

19.

Koike R, Nishimura T, Yasumizu R, Tanaka H, Hataba Y, Watanabe T . The splenic marginal zone is absent in alymphoplastic aly mutant mice. Eur J Immunol. 1996; 26(3):669-75. DOI: 10.1002/eji.1830260324. View

20.

Doppler H, Liou G, Storz P . Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. PLoS One. 2013; 8(1):e53676. PMC: 3536768. DOI: 10.1371/journal.pone.0053676. View