NFKBIZ

NF-kappa-B inhibitor zeta (IκBζ) is a protein that in humans is encoded by the NFKBIZ gene.^[5][6][7] This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-B proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene.^[8]

NFKBIZ
Identifiers
Aliases	NFKBIZ, IKBZ, INAP, MAIL, NFKB inhibitor zeta
External IDs	OMIM: 608004 MGI: 1931595 HomoloGene: 12734 GeneCards: NFKBIZ
Gene location (Human) Chr. Chromosome 3 (human)^[1] Band 3q12.3 Start 101,827,991 bp^[1] End 101,861,022 bp^[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)^[2] Band 16|16 C1.1 Start 55,631,738 bp^[2] End 55,659,262 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pancreatic epithelial cell pancreatic ductal cell palpebral conjunctiva parietal pleura trachea visceral pleura bone marrow cells gastric mucosa monocyte nipple Top expressed in Paneth cell islet of Langerhans conjunctival fornix mucous cell of stomach left lung lobe jejunum duodenum secondary oocyte cervix epithelium of stomach More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding transcription coregulator activity Cellular component nucleus nuclear speck cytoplasmic ribonucleoprotein granule Biological process regulation of transcription by RNA polymerase II inflammatory response regulation of transcription, DNA-templated transcription, DNA-templated T cell receptor signaling pathway positive regulation of T-helper 17 cell differentiation positive regulation of inflammatory response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 64332 80859 Ensembl ENSG00000144802 ENSMUSG00000035356 UniProt Q9BYH8 Q9EST8 RefSeq (mRNA) NM_031419 NM_001005474 NM_001159394 NM_001159395 NM_030612 RefSeq (protein) NP_001005474 NP_113607 NP_001152866 NP_001152867 NP_085115 Location (UCSC) Chr 3: 101.83 – 101.86 Mb Chr 16: 55.63 – 55.66 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical relevance

NFKBIZ has been implicated as an oncogene in diffuse large B-cell lymphoma (DLBCL). Specifically, genomic locus containing this gene is recurrently amplified in copy number in the activated B-cell (ABC) subgroup of DLBCL.^[9] More recently, a recurrence of somatic mutations affecting the 3-prime untranslated region of NFKBIZ were found to promote NFKBIZ expression in ABC DLBCL.^[10]

IκBζ is required for expression of the SASP CCL2 (MCP1) cytokine, which recruits macrophages to remove cancer cells.^[7]

The flavonoid apigenin has been shown to reduce gene expression of IκBζ.^[11]

References

1. GRCh38: Ensembl release 89: ENSG00000144802 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000035356 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Eto A, Muta T, Yamazaki S, Takeshige K (February 2003). "Essential roles for NF-kappa B and a Toll/IL-1 receptor domain-specific signal(s) in the induction of I kappa B-zeta". Biochemical and Biophysical Research Communications. 301 (2): 495–501. doi:10.1016/S0006-291X(02)03082-6. PMID 12565889.
6. Totzke G, Essmann F, Pohlmann S, Lindenblatt C, Jänicke RU, Schulze-Osthoff K (May 2006). "A novel member of the IkappaB family, human IkappaB-zeta, inhibits transactivation of p65 and its DNA binding". The Journal of Biological Chemistry. 281 (18): 12645–54. doi:10.1074/jbc.M511956200. PMID 16513645.
7. Alexander E, Hildebrand DG, Schulze-Osthoff K, Essmann F (2013). "IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence". Journal of Cell Science. 126 (Pt 16): 3738–3745. doi:10.1242/jcs.128835. PMID 23781024.
8. "Entrez Gene: NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta".
9. Nogai H, Wenzel SS, Hailfinger S, Grau M, Kaergel E, Seitz V, et al. (September 2013). "IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL". Blood. 122 (13): 2242–50. doi:10.1182/blood-2013-06-508028. PMID 23869088. S2CID 18427175.
10. Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK, et al. (October 2018). "Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma". Nature Communications. 9 (1): 4001. Bibcode:2018NatCo...9.4001A. doi:10.1038/s41467-018-06354-3. PMC 6167379. PMID 30275490.
11. Lim H, Heo MY, Kim HP (2019). "Flavonoids: Broad Spectrum Agents on Chronic Inflammation". Biomolecules & Therapeutics. 27 (3): 241–253. doi:10.4062/biomolther.2019.034. PMC 6513185. PMID 31006180.

Further reading

• Kitamura H, Kanehira K, Okita K, Morimatsu M, Saito M (November 2000). "MAIL, a novel nuclear I kappa B protein that potentiates LPS-induced IL-6 production". FEBS Letters. 485 (1): 53–6. doi:10.1016/S0014-5793(00)02185-2. PMID 11086164. S2CID 85416608.
• Shiina T, Morimatsu M, Kitamura H, Ito T, Kidou S, Matsubara K, Matsuda Y, Saito M, Syuto B (October 2001). "Genomic organization, chromosomal localization, and promoter analysis of the mouse Mail gene". Immunogenetics. 53 (8): 649–55. doi:10.1007/s00251-001-0376-x. PMID 11797098. S2CID 12387932.
• Haruta H, Kato A, Todokoro K (April 2001). "Isolation of a novel interleukin-1-inducible nuclear protein bearing ankyrin-repeat motifs". The Journal of Biological Chemistry. 276 (16): 12485–8. doi:10.1074/jbc.C100075200. PMID 11278262.
• Yamazaki S, Muta T, Takeshige K (July 2001). "A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei". The Journal of Biological Chemistry. 276 (29): 27657–62. doi:10.1074/jbc.M103426200. PMID 11356851.
• Kitamura H, Kanehira K, Shiina T, Morimatsu M, Jung BD, Akashi S, Saito M (May 2002). "Bacterial lipopolysaccharide induces mRNA expression of an IkappaB MAIL through toll-like receptor 4". The Journal of Veterinary Medical Science. 64 (5): 419–22. doi:10.1292/jvms.64.419. PMID 12069074.
• Kitamura H, Matsushita Y, Iwanaga T, Mori K, Kanehira K, Fujikura D, Morimatsu M, Saito M (March 2003). "Bacterial lipopolysaccharide-induced expression of the IkappaB protein MAIL in B-lymphocytes and macrophages". Archives of Histology and Cytology. 66 (1): 53–62. doi:10.1679/aohc.66.53. PMID 12703554.
• Shiina T, Konno A, Oonuma T, Kitamura H, Imaoka K, Takeda N, Todokoro K, Morimatsu M (December 2004). "Targeted disruption of MAIL, a nuclear IkappaB protein, leads to severe atopic dermatitis-like disease". The Journal of Biological Chemistry. 279 (53): 55493–8. doi:10.1074/jbc.M409770200. PMID 15491998.
• Ito T, Morimatsu M, Oonuma T, Shiina T, Kitamura H, Syuto B (November 2004). "Transcriptional regulation of the MAIL gene in LPS-stimulated RAW264 mouse macrophages". Gene. 342 (1): 137–43. doi:10.1016/j.gene.2004.07.032. PMID 15527973.
• Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K, Kaisho T, Kuwata H, Takeuchi O, Takeshige K, Saitoh T, Yamaoka S, Yamamoto N, Yamamoto S, Muta T, Takeda K, Akira S (July 2004). "Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta". Nature. 430 (6996): 218–22. Bibcode:2004Natur.430..218Y. doi:10.1038/nature02738. PMID 15241416. S2CID 4384768.
• Yamaji D, Kitamura H, Kimura K, Matsushita Y, Okada H, Shiina T, Morimatsu M, Saito M (April 2004). "Cloning of bovine MAIL and its mRNA expression in white blood cells of Holstein cows". Veterinary Immunology and Immunopathology. 98 (3–4): 175–84. doi:10.1016/j.vetimm.2003.12.004. PMID 15010226.
• Yamazaki S, Muta T, Matsuo S, Takeshige K (January 2005). "Stimulus-specific induction of a novel nuclear factor-kappaB regulator, IkappaB-zeta, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization". The Journal of Biological Chemistry. 280 (2): 1678–87. doi:10.1074/jbc.M409983200. PMID 15522867.
• Motoyama M, Yamazaki S, Eto-Kimura A, Takeshige K, Muta T (March 2005). "Positive and negative regulation of nuclear factor-kappaB-mediated transcription by IkappaB-zeta, an inducible nuclear protein". The Journal of Biological Chemistry. 280 (9): 7444–51. doi:10.1074/jbc.M412738200. PMID 15618216.
• Cowland JB, Muta T, Borregaard N (May 2006). "IL-1beta-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IkappaB-zeta". Journal of Immunology. 176 (9): 5559–66. doi:10.4049/jimmunol.176.9.5559. PMID 16622025.
• Oonuma T, Morimatsu M, Ochiai K, Iwanaga T, Hashizume K (March 2007). "Role of NF-kappaB in constitutive expression of MAIL in epidermal keratinocytes". The Journal of Veterinary Medical Science. 69 (3): 279–84. doi:10.1292/jvms.69.279. PMID 17409644.
• Matsuo S, Yamazaki S, Takeshige K, Muta T (August 2007). "Crucial roles of binding sites for NF-kappaB and C/EBPs in IkappaB-zeta-mediated transcriptional activation". The Biochemical Journal. 405 (3): 605–15. doi:10.1042/BJ20061797. PMC 2267307. PMID 17447895.