Q04207 (TF65_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified May 29, 2013. Version 148. History...
Names and origin
|Protein names||Recommended name:|
Transcription factor p65
Nuclear factor NF-kappa-B p65 subunit
Nuclear factor of kappa light polypeptide gene enhancer in B-cells 3
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||549 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression By similarity. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Ref.14 Ref.15
Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds AES and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1. Interacts with NFKBIA. Interacts with GSK3B. Interacts with NFKBIB. Interacts with NFKBIE. Interacts with NFKBIZ. Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, IKBKAP and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at 'Thr-254') with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with MTDH and PHF11. Interacts with NFKBID. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is associated with a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1 By similarity. Interacts with UFL1 and COMMD1 By similarity. Interacts with BRMS1; this promotes deacetylation of 'Lys-310' By similarity. Interacts with EHMT1 (via ANK repeats). Interacts with NOTCH2. Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation By similarity. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA By similarity. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Ref.5 Ref.6 Ref.7 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14
Nucleus. Cytoplasm. Note: Colocalized with DDX1 in the nucleus upon TNF-alpha induction By similarity. Nuclear, but also found in the cytoplasm in an inactive form complexed to an inhibitor (I-kappa-B). Colocalizes with GFI1 in the nucleus after lipopolysaccharide (LPS) stimulation. Ref.14
Ubiquitinated, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response By similarity.
Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes. Ref.14
Phosphorylation on Ser-534 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity By similarity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities. Ref.8 Ref.14
Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2 By similarity.
S-nitrosylation of Cys-38 inactivates the enzyme activity.
Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity.
Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B By similarity.
Contains 1 RHD (Rel-like) domain.
|EHMT1||Q9H9B1||5||EBI-644400,EBI-766087||From a different organism.|
|SETD6||Q8TBK2||4||EBI-644400,EBI-3863032||From a different organism.|
|SETD7||Q8WTS6||2||EBI-644400,EBI-1268586||From a different organism.|
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform p65 (identifier: Q04207-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform p65 delta (identifier: Q04207-2) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 549||549||Transcription factor p65||PRO_0000205170|
|Domain||19 – 306||288||RHD|
|Motif||301 – 304||4||Nuclear localization signal Potential|
Amino acid modifications
|Modified residue||38||1||Cysteine persulfide; alternate Ref.15|
|Modified residue||38||1||S-nitrosocysteine; alternate Ref.15|
|Modified residue||122||1||N6-acetyllysine; by PCAF and EP300; alternate By similarity|
|Modified residue||123||1||N6-acetyllysine; by PCAF and EP300; alternate By similarity|
|Modified residue||254||1||Phosphothreonine By similarity|
|Modified residue||276||1||Phosphoserine; by RPS6KA4 and RPS6KA5 By similarity|
|Modified residue||310||1||N6-acetyllysine; alternate By similarity|
|Modified residue||310||1||N6-methyllysine; by SETD6 Ref.14|
|Modified residue||311||1||Phosphoserine; by PKC/PRKCZ Ref.8 Ref.14|
|Modified residue||433||1||Phosphothreonine By similarity|
|Modified residue||467||1||Phosphoserine; by IKKB and IKKE By similarity|
|Modified residue||504||1||Phosphothreonine; by CHEK1 By similarity|
|Modified residue||527||1||Phosphoserine; by CK2 By similarity|
|Modified residue||534||1||Phosphoserine; by IKKB By similarity|
|Cross-link||37||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO3) By similarity|
|Cross-link||122||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO3); alternate By similarity|
|Cross-link||123||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO3); alternate By similarity|
|Alternative sequence||222 – 231||10||Missing in isoform p65 delta.||VSP_005589|
|Mutagenesis||38||1||C → S: Abolishes sulfhydration and impairs interaction with RPS3. Ref.15|
|Mutagenesis||281||1||S → A or E: Abolishes DNA-binding and transcriptional activity. Ref.9|
|Mutagenesis||310||1||K → R: Abolishes monomethylation by SETD6 and interaction with EHMT1. Ref.14|
|Sequence conflict||28||1||K → N in AAB00795. Ref.3|
|Sequence conflict||61||1||I → IQKD in AAB00795. Ref.3|
Helix Strand Turn
|Beta strand||20 – 25||6|
|Beta strand||30 – 32||3|
|Turn||37 – 39||3|
|Beta strand||48 – 50||3|
|Beta strand||53 – 55||3|
|Beta strand||60 – 65||6|
|Beta strand||71 – 77||7|
|Beta strand||79 – 82||4|
|Beta strand||87 – 92||6|
|Beta strand||99 – 103||5|
|Beta strand||109 – 112||4|
|Beta strand||117 – 120||4|
|Helix||123 – 125||3|
|Helix||126 – 135||10|
|Turn||145 – 148||4|
|Beta strand||156 – 166||11|
|Beta strand||168 – 174||7|
|Beta strand||178 – 184||7|
|Beta strand||186 – 188||3|
|Turn||189 – 191||3|
|Beta strand||196 – 200||5|
|Beta strand||202 – 205||4|
|Beta strand||211 – 217||7|
|Helix||221 – 223||3|
|Beta strand||225 – 230||6|
|Beta strand||233 – 236||4|
|Helix||241 – 243||3|
|Beta strand||248 – 253||6|
|Beta strand||266 – 274||9|
|Turn||275 – 278||4|
|Beta strand||284 – 289||6|
|Helix||294 – 304||11|
|Helix||306 – 315||10|
|||"DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide."|
Nolan G.P., Ghosh S., Liou H.C., Tempst P., Baltimore D.
Cell 64:961-969(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P65).
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P65).
Tissue: Mammary gland.
|||"Cloning of the murine relA (p65 NF-kappa B) gene and comparison to the human gene reveals a distinct first intron."|
Linker R.A., Baeuerle P.A., Kaltschmidt C.
Gene 176:119-124(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114.
|||"Genomic organization of the gene encoding the p65 subunit of NF-kappa B: multiple variants of the p65 protein may be generated by alternative splicing."|
Deloukas P., van Loon A.P.G.M.
Hum. Mol. Genet. 2:1895-1900(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 188-252, ALTERNATIVE SPLICING.
|||"Role of unphosphorylated, newly synthesized IkappaB beta in persistent activation of NF-kappaB."|
Suyang H., Phillips R.J., Douglas I., Ghosh S.
Mol. Cell. Biol. 16:5444-5449(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NFKBIB.
|||"Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP."|
Spencer E., Jiang J., Chen Z.J.
Genes Dev. 13:284-294(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NFKBIA.
|||"Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor."|
Fiorini E., Schmitz I., Marissen W.E., Osborn S.L., Touma M., Sasada T., Reche P.A., Tibaldi E.V., Hussey R.E., Kruisbeek A.M., Reinherz E.L., Clayton L.K.
Mol. Cell 9:637-648(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NFKBID.
|||"Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation."|
Duran A., Diaz-Meco M.T., Moscat J.
EMBO J. 22:3910-3918(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-311.
|||"Critical role of RelB serine 368 for dimerization and p100 stabilization."|
Maier H.J., Marienfeld R., Wirth T., Baumann B.
J. Biol. Chem. 278:39242-39250(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF SER-281.
|||"A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells."|
Goriely S., Van Lint C., Dadkhah R., Libin M., De Wit D., Demonte D., Willems F., Goldman M.
J. Exp. Med. 199:1011-1016(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN THE NF-KAPPA-B P65-P50 COMPLEX, IDENTIFICATION IN THE NF-KAPPA-B P65-P65 COMPLEX.
|||"Tumor necrosis factor alpha induction of NF-kappaB requires the novel coactivator SIMPL."|
Kwon H.-J., Breese E.H., Vig-Varga E., Luo Y., Lee Y., Goebl M.G., Harrington M.A.
Mol. Cell. Biol. 24:9317-9326(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IRAK1BP1.
|||"Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression."|
Covic M., Hassa P.O., Saccani S., Buerki C., Meier N.I., Lombardi C., Imhof R., Bedford M.T., Natoli G., Hottiger M.O.
EMBO J. 24:85-96(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CARM1.
|||"The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis."|
Fukushima H., Nakao A., Okamoto F., Shin M., Kajiya H., Sakano S., Bigas A., Jimi E., Okabe K.
Mol. Cell. Biol. 28:6402-6412(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NOTCH2.
|||"Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling."|
Levy D., Kuo A.J., Chang Y., Schaefer U., Kitson C., Cheung P., Espejo A., Zee B.M., Liu C.L., Tangsombatvisit S., Tennen R.I., Kuo A.Y., Tanjing S., Cheung R., Chua K.F., Utz P.J., Shi X., Prinjha R.K. Gozani O.
Nat. Immunol. 12:29-36(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, METHYLATION AT LYS-310, PHOSPHORYLATION AT SER-311, INTERACTION WITH EHMT1, MUTAGENESIS OF LYS-310.
|||"Hydrogen sulfide-linked sulfhydration of NF-kappaB mediates its antiapoptotic actions."|
Sen N., Paul B.D., Gadalla M.M., Mustafa A.K., Sen T., Xu R., Kim S., Snyder S.H.
Mol. Cell 45:13-24(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SULFHYDRATION AT CYS-38, S-NITROSYLATION AT CYS-38, MUTAGENESIS OF CYS-38.
|||"The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation."|
Huxford T., Huang D.B., Malek S., Ghosh G.
Cell 95:759-770(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 19-291.
|||"A novel DNA recognition mode by the NF-kappa B p65 homodimer."|
Chen Y.Q., Ghosh S., Ghosh G.
Nat. Struct. Biol. 5:67-73(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 19-291.
|||"Crystal structure of p50/p65 heterodimer of transcription factor NF-kappaB bound to DNA."|
Chen F.E., Huang D.B., Chen Y.Q., Ghosh G.
Nature 391:410-413(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
|+||Additional computationally mapped references.|
|M61909 mRNA. Translation: AAA39811.1.|
BC003818 mRNA. Translation: AAH03818.1.
L77155 Genomic DNA. Translation: AAB00795.1.
Z22952 Genomic DNA. Translation: CAA80528.1.
|RefSeq||NP_033071.1. NM_009045.4. |
3D structure databases
|SMR||Q04207. Positions 20-325. |
Protein-protein interaction databases
|IntAct||Q04207. 15 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000025867; ENSMUSP00000025867; ENSMUSG00000024927. |
|UCSC||uc008gee.1. mouse. |
|MGI||MGI:103290. Rela. |
Gene expression databases
|GermOnline||ENSMUSG00000024927. Mus musculus. |
Family and domain databases
|Gene3D||188.8.131.52. 1 hit. |
184.108.40.2060. 1 hit.
|InterPro||IPR013783. Ig-like_fold. |
|Pfam||PF00554. RHD. 1 hit. |
|PRINTS||PR00057. NFKBTNSCPFCT. |
|SMART||SM00429. IPT. 1 hit. |
|SUPFAM||SSF81296. Ig_E-set. 1 hit. |
SSF49417. P53_like_DNA_bnd. 1 hit.
|PROSITE||PS01204. REL_1. 1 hit. |
PS50254. REL_2. 1 hit.
|ChiTaRS||RELA. mouse. |
|Accession||Primary (citable) accession number: Q04207|
Secondary accession number(s): Q62025
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|