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|Coordinate||135,626,611 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105|
|Synonym(s)||p50 subunit of NF kappaB, nuclear factor kappaB p50, NF-kappaB, NF-kappaB p50, p50, p50/p105, NF kappaB1|
|Chromosomal Location||135,584,655-135,691,547 bp (-)|
|MGI Phenotype||Strain: 1857225
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappa-B (NFKB) protein complex. NFKB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth. Alternative splicing results in multiple transcript variants encoding different isoforms, at least one of which is proteolytically processed. [provided by RefSeq, Feb 2016]
PHENOTYPE: Homozygous null mice have a decreased survivor rate, abnormal T cell development and decreased number of peripheral T cells, abnormal humoral responses with decreased immunoglobulin class switching, exhibit mild organ inflammation, and are susceptible toboth bacterial infections and hearing loss. [provided by MGI curators]
|Amino Acid Change||Lysine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000029812] [ENSMUSP00000128345] [ENSMUSP00000143601]|
AA Change: K128*
|Predicted Effect||probably null|
AA Change: K128*
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2018-07-20 12:11 PM by Diantha La Vine|
|Record Created||2017-09-09 4:17 PM by Bruce Beutler|
The kookaburra phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5434, some of which showed reduced frequencies of central memory CD4 T cells in CD4 T cells (Figure 1) and naive CD8 T cells in CD8 T cells (Figure 2) with concomitant increased frequencies of central memory CD8 T cells in CD8 T cells (Figure 3), all in the peripheral blood. Expression of CD44 on peripheral blood CD8 T cells was increased (Figure 4). The serum levels of total IgE were also reduced (Figure 5).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 56 mutations. All of the above phenotypes were linked by continuous variable mapping to a mutation in Nfkb1: an A to T transversion at base pair 135,626,611 (v38) on chromosome 3, corresponding to base pair 65,372 in the GenBank genomic region NC_000069 encoding Nfkb1. The strongest association was found with a recessive model of inheritance to the normalized frequency of central memory CD8 T cells in CD8 T cells, wherein five variant homozygotes departed phenotypically from 16 homozygous reference mice and 35 heterozygous mice with a P value of 7.573 x 10-16 (Figure 6).
The mutation corresponds to residue 884 in the mRNA sequence NM_178666 within exon 7 of 25 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of lysine 128 for a premature stop codon (K128*) in the NF-κB1 protein.
NF-κB1 (alternatively, p50/p105) is a member of the NF-κB protein family that are characterized by an N-terminal Rel homology domain (RHD), a glycine rich region (GRR), an ankyrin repeat domain (ARD), a death domain (DD), and a PEST motif [Figure 7 & 8; reviewed in (1)]. The p105 precursor protein can be proteolytically processed to generate p50 (i.e., amino acids 1-430 of p105). The RHD (amino acids 42-240, SMART) is comprised of the N-terminal domain, the dimerization domain (DimD), and a nuclear localization sequence that mediate DNA binding, nuclear localization, and subunit dimerization [reviewed in (1)]. The p50 RHD mediates co-translational dimerization with p105 and this dimerization is necessary for efficient p50 production (2;3). The GRR (amino acids 400-475 (4); 370-392, UniProt) is essential for the constitutive processing of p105 to p50 as well as for stabilization of the p50 subunit (2;5;6). Cohen et al. described a processing inhibitory domain (PID; aa 474-544) downstream of the GRR and upstream of the ARD that functions to regulate the constitutive processing of p105 (7). The ARD is at the C-terminus of p105 (amino acids 507-743, SMART) and has seven ankyrin motifs [reviewed in (1)]. The DD of p105 (aa 801-888, UniProt) is essential for IKK1 and IKK2-mediated phosphorylation of the p105 PEST motif by acting as a docking site for IKK (8;9). The PEST motif contains a conserved motif (Asp-Ser927-Gly-Val-Gly-Thr-Ser932) homologous to the IKK target sequence in IκBα [reviewed in (10)]. The kookaburra mutation results in substitution of lysine 128 for a premature stop codon (K128*) in the NF-κB1 protein; residue 128 is within the RHD.
For more information about Nfkb1, please see the record for Finlay.
NF-κB1 (p50 and p105) can form homodimers or heterodimers with c-Rel, RelA (p65), NF-κB2 (p52 and its precursor p100; see the record for xander), or RelB (11). The p105 precursor can act as an inhibitor of NF-κB dimers through both a direct dimerization to the NF-κB polypeptides as well as through interactions with preformed dimers (12). After agonist stimulation, p105 is degraded, facilitating the release of associated Rel subunits (i.e., RelA, c-Rel, and p50) and the translocation of the Rel subunits from the cytoplasm into the nucleus; RelB is not retained in the cytoplasm by p105 (13-16). In addition, p105 and IκBγ can associate with NF-κB dimers and prevent them from translocating to the nucleus (17). The p50 homodimer can bind to both nucleosomal DNA as well as naked DNA, facilitating the regulation of genes at sites of transcriptionally repressed chromatin as well as genes found in transcriptionally active chromatin (18). Depending on the cell type, the p50 homodimer can act as either a transcriptional activator or a repressor [reviewed in (10)]. The p50 homodimer typically binds DNA in unstimulated cells to repress NF-κB-dependent gene transcription (19). After stimulation, p50 homodimers can also function as transcriptional activators by an association of the homodimer with transcriptional co-activators.
A variety of stimuli (e.g., cytokines, ultraviolet irradiation, and viral products) activate NF-κB complexes and the translocation of the activated complexes to the nucleus. In the nucleus, NF-κB acts as a transcription factor that regulates the expression of genes encoding a variety of immune response genes including pro-inflammatory cytokines (e.g., TNFα (see the record for PanR1), IL-1, and IL-6), chemokines [e.g., MIP-1α (macrophage inflammatory protein-1α) and RANTES (regulated upon activation, normal T-cell expressed and secreted)], cell adhesion molecules [e.g., E-selectin and VCAM-1 (vascular cell adhesion molecule-1)], effector molecules [e.g., defensins], enzymes [e.g., inducible nitric oxide synthase], and growth factors to regulate the recruitment of immune cells to the site of infection [(20;21); reviewed in (10)]. Inhibition of NF-κB leads to apoptosis [through the misregulation of anti-apoptotic proteins (e.g., c-IAP-1/2, AI, Bcl-2 and Bcl-XL)], delayed cell growth, reduced cell proliferation [through negative regulation of cell cycle regulator cyclin D1 (22)] and incorrect immune cell development [reviewed in (23-25)]. Please see the record for xander for additional details about NF-κB signaling.
The phenotypes observed in the kookaburra mice indicate loss of NF-κB1kookaburra function.
kookaburra(F):5'- TTGTCTCAGGCAGGACAGATATC -3'
kookaburra(R):5'- TCCATGTTACAGTCAGGTCAGATG -3'
kookaburra_seq(F):5'- CTCTATTTCCTTAGCAGTTCAAAGG -3'
kookaburra_seq(R):5'- ACAGTCAGGTCAGATGTACTAAC -3'
1. Pereira, S. G., and Oakley, F. (2008) Nuclear Factor-kappaB1: Regulation and Function. Int J Biochem Cell Biol. 40, 1425-1430.
2. Lin, L., DeMartino, G. N., and Greene, W. C. (1998) Cotranslational Biogenesis of NF-kappaB p50 by the 26S Proteasome. Cell. 92, 819-828.
3. Lin, L., DeMartino, G. N., and Greene, W. C. (2000) Cotranslational Dimerization of the Rel Homology Domain of NF-kappaB1 Generates p50-p105 Heterodimers and is Required for Effective p50 Production. EMBO J. 19, 4712-4722.
4. Lin, L., and Kobayashi, M. (2003) Stability of the Rel Homology Domain is Critical for Generation of NF-Kappa B p50 Subunit. J Biol Chem. 278, 31479-31485.
5. Moorthy, A. K., Savinova, O. V., Ho, J. Q., Wang, V. Y., Vu, D., and Ghosh, G. (2006) The 20S Proteasome Processes NF-kappaB1 p105 into p50 in a Translation-Independent Manner. EMBO J. 25, 1945-1956.
6. Lee, C., Schwartz, M. P., Prakash, S., Iwakura, M., and Matouschek, A. (2001) ATP-Dependent Proteases Degrade their Substrates by Processively Unraveling them from the Degradation Signal. Mol Cell. 7, 627-637.
7. Cohen, S., Lahav-Baratz, S., and Ciechanover, A. (2006) Two Distinct Ubiquitin-Dependent Mechanisms are Involved in NF-kappaB p105 Proteolysis. Biochem Biophys Res Commun. 345, 7-13.
8. Beinke, S., Belich, M. P., and Ley, S. C. (2002) The Death Domain of NF-Kappa B1 p105 is Essential for Signal-Induced p105 Proteolysis. J Biol Chem. 277, 24162-24168.
9. Heissmeyer, V., Krappmann, D., Wulczyn, F. G., and Scheidereit, C. (1999) NF-kappaB p105 is a Target of IkappaB Kinases and Controls Signal Induction of Bcl-3-p50 Complexes. EMBO J. 18, 4766-4778.
10. Beinke, S., and Ley, S. C. (2004) Functions of NF-kappaB1 and NF-kappaB2 in Immune Cell Biology. Biochem J. 382, 393-409.
11. Urban, M. B., Schreck, R., and Baeuerle, P. A. (1991) NF-Kappa B Contacts DNA by a Heterodimer of the p50 and p65 Subunit. EMBO J. 10, 1817-1825.
12. Savinova, O. V., Hoffmann, A., and Ghosh, G. (2009) The Nfkb1 and Nfkb2 Proteins p105 and p100 Function as the Core of High-Molecular-Weight Heterogeneous Complexes. Mol Cell. 34, 591-602.
13. Mercurio, F., DiDonato, J. A., Rosette, C., and Karin, M. (1993) P105 and p98 Precursor Proteins Play an Active Role in NF-Kappa B-Mediated Signal Transduction. Genes Dev. 7, 705-718.
14. Solan, N. J., Miyoshi, H., Carmona, E. M., Bren, G. D., and Paya, C. V. (2002) RelB Cellular Regulation and Transcriptional Activity are Regulated by p100. J Biol Chem. 277, 1405-1418.
15. Rice, N. R., MacKichan, M. L., and Israel, A. (1992) The Precursor of NF-Kappa B p50 has I Kappa B-Like Functions. Cell. 71, 243-253.
16. Naumann, M., Wulczyn, F. G., and Scheidereit, C. (1993) The NF-Kappa B Precursor p105 and the Proto-Oncogene Product Bcl-3 are I Kappa B Molecules and Control Nuclear Translocation of NF-Kappa B. EMBO J. 12, 213-222.
17. Perkins, N. D. (2007) Integrating Cell-Signalling Pathways with NF-kappaB and IKK Function. Nat Rev Mol Cell Biol. 8, 49-62.
18. Angelov, D., Lenouvel, F., Hans, F., Muller, C. W., Bouvet, P., Bednar, J., Moudrianakis, E. N., Cadet, J., and Dimitrov, S. (2004) The Histone Octamer is Invisible when NF-kappaB Binds to the Nucleosome. J Biol Chem. 279, 42374-42382.
19. Zhong, H., May, M. J., Jimi, E., and Ghosh, S. (2002) The Phosphorylation Status of Nuclear NF-Kappa B Determines its Association with CBP/p300 Or HDAC-1. Mol Cell. 9, 625-636.
20. Chen, F., Castranova, V., Shi, X., and Demers, L. M. (1999) New Insights into the Role of Nuclear Factor-kappaB, a Ubiquitous Transcription Factor in the Initiation of Diseases. Clin Chem. 45, 7-17.
21. Zhang, G., and Ghosh, S. (2001) Toll-Like Receptor-Mediated NF-kappaB Activation: A Phylogenetically Conserved Paradigm in Innate Immunity. J Clin Invest. 107, 13-19.
22. Nakamura, Y., Grumont, R. J., and Gerondakis, S. (2002) NF-kappaB1 can Inhibit v-Abl-Induced Lymphoid Transformation by Functioning as a Negative Regulator of Cyclin D1 Expression. Mol Cell Biol. 22, 5563-5574.
23. Karin, M., and Lin, A. (2002) NF-kappaB at the Crossroads of Life and Death. Nat Immunol. 3, 221-227.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Xue Zhong, Jin Huk Choi, and Bruce Beutler|
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