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P41183 (BCL6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 126. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
B-cell lymphoma 6 protein homolog
Gene names
Name:Bcl6
Synonyms:Bcl-6
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length707 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcriptional repressor mainly required for germinal center (GC) formation and antibody affinity maturation which has different mechanisms of action specific to the lineage and biological functions. Forms complexes with different corepressors and histone deacetylases to repress the transcriptional expression of different subsets of target genes. Represses its target genes by binding directly to the DNA sequence 5'-TTCCTAGAA-3' (BCL6-binding site) or indirectly by repressing the transcriptional activity of transcription factors. In GC B-cells, represses genes that function in differentiation, inflammation, apoptosis and cell cycle control, also autoregulates its transcriptional expression and up-regulates, indirectly, the expression of some genes important for GC reactions, such as AICDA, through the repression of microRNAs expression, like miR155. An important function is to allow GC B-cells to proliferate very rapidly in response to T-cell dependent antigens and tolerate the physiological DNA breaks required for immunglobulin class switch recombination and somatic hypermutation without inducing a p53/TP53-dependent apoptotic response. In follicular helper CD4+ T-cells (T(FH) cells), promotes the expression of T(FH)-related genes but inhibits the differentiation of T(H)1, T(H)2 and T(H)17 cells. Also required for the establishment and maintenance of immunological memory for both T- and B-cells. Suppresses macrophage proliferation through competition with STAT5 for STAT-binding motifs binding on certain target genes, such as CCL2 and CCND2. In response to genotoxic stress, controls cell cycle arrest in GC B-cells in both p53/TP53-dependedent and -independent manners. Besides, also controls neurogenesis through the alteration of the composition of NOTCH-dependent transcriptional complexes at selective NOTCH targets, such as HES5, including the recruitment of the deacetylase SIRT1 and resulting in an epigenetic silencing leading to neuronal differentiation. Ref.6 Ref.7 Ref.9 Ref.10 Ref.12

Subunit structure

Homodimer. Interacts (via BTB domain) with the corepressors BCOR, NCOR1 and SMRT/NCOR2; the interactions are direct. Forms preferably ternary complexes with BCOR and SMRT/NCOR2 on target gene promoters but, on enhancer elements, interacts with SMRT/NCOR2 and HDAC3 to repress proximal gene expression. Interacts with histone deacetylases HDAC2, HDAC5 and HDAC9 (via the catalytic domain). Interacts with ZBTB7 and BCL6B. Interacts with SCF(FBXO11) complex; the interaction is independent of phosphorylation and promotes ubiquitination. Interacts (when phosphorylated) with PIN1; the interaction is required for BCL6 degradation upon genotoxic stress. Interacts with ZBTB17; inhibits ZBTB17 transcriptional activity. Interacts with CTBP1, autoinhibits its transcriptional expression. Interacts with NOTCH1 NCID and SIRT1; leads to a epigenetic repression of selective NOTCH1-target genes. Interacts (nor via BTB domain neither acetylated) with the NuRD complex components CHD4, HDAC1, MBD3 and MTA3; the interaction with MTA3 inhibits BCL6 acetylation and is required for BCL6 transpriptional repression. Ref.4 Ref.5 Ref.10 Ref.12

Subcellular location

Nucleus Ref.5.

Tissue specificity

Expressed at least in germinal center B-cells of spleen. Ref.8 Ref.9

Developmental stage

Detected in the cerebral cortex from 12.5 dpc until birth, with highest levels in the frontal and parietal parts of the neocortex than the occipital parts. Ref.10

Domain

Interaction with corepressors through the BTB domain is needed to facilitate the rapid proliferation and survival of GC B-cells but is not involved in the T(FH) formation and BCL6-mediated suppression of T(H)2 and T(H)17 differentiation required for GC formation (Ref.12). Ref.12

Post-translational modification

Phosphorylated by MAPK1 in response to antigen receptor activation at Ser-334 and Ser-344. Phosphorylated by ATM in response to genotoxic stress. Phosphorylation induces its degradation by ubiquitin/proteasome pathway By similarity.

Polyubiquitinated. Polyubiquitinated by SCF(FBXO11), leading to its degradation by the proteasome By similarity.

Acetylated at Lys-380 by EP300 which inhibits the interaction with NuRD complex and the transcriptional repressor function. Deacetylated by HDAC- and SIR2-dependent pathways By similarity.

Disruption phenotype

More than 50% of lethality by 6 weeks of age. Mice have infiltrates of inflammatory cells in their lungs, as well as multinodular lesions with eosinophil infiltrations into the spleen, significantly more T(H)2 and T(H)17 cells and up-regulated levels of inflammtaroy chemokines in macrophages, but, express low levels of memory CD8+ T-cells and, in spleen, GC B and T(FH) cells are both undetectable. B-cells express 10-fold lower levels of surface IgM than control littermates and macrophages divide faster. From 12.5 dpc to at least 21 days after birth, animals have reduced size of the cerebral hemispheres and a reduced thickness of the frontal and parietal cortex with all the cortical layers affected. At 12.5 and 15.5 dpc, marked reduction of cell-cyle exit indicating defective transition from neural progenitor Cells to postmitotic neurons. Ref.6 Ref.7 Ref.10 Ref.12

Sequence similarities

Contains 1 BTB (POZ) domain.

Contains 6 C2H2-type zinc fingers.

Ontologies

Keywords
   Biological processImmunity
Inflammatory response
Transcription
Transcription regulation
   Cellular componentNucleus
   DomainRepeat
Zinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionActivator
Repressor
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred from genetic interaction PubMed 14647274. Source: MGI

Rho protein signal transduction

Inferred from genetic interaction PubMed 15860730. Source: MGI

actin cytoskeleton organization

Inferred from mutant phenotype PubMed 15860730. Source: MGI

cell morphogenesis

Inferred from mutant phenotype PubMed 15860730. Source: MGI

cellular response to DNA damage stimulus

Inferred from electronic annotation. Source: Ensembl

erythrocyte development

Inferred from mutant phenotype PubMed 15661395. Source: MGI

germinal center formation

Inferred from mutant phenotype PubMed 12354385PubMed 9110977PubMed 9171827PubMed 9236196. Source: MGI

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of Rho protein signal transduction

Inferred from mutant phenotype PubMed 15860730. Source: MGI

negative regulation of T-helper 2 cell differentiation

Inferred from genetic interaction PubMed 12594267. Source: MGI

negative regulation of apoptotic process

Inferred from direct assay PubMed 9927203. Source: MGI

negative regulation of cell differentiation

Inferred from mutant phenotype PubMed 15240705. Source: MGI

negative regulation of cell growth

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from mutant phenotype PubMed 15507530PubMed 15611242. Source: MGI

negative regulation of cell-matrix adhesion

Inferred from mutant phenotype PubMed 15860730. Source: MGI

negative regulation of isotype switching to IgE isotypes

Inferred from mutant phenotype PubMed 10490661. Source: MGI

negative regulation of mast cell cytokine production

Inferred from mutant phenotype PubMed 15950739. Source: MGI

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 10490661PubMed 12097386PubMed 12817026PubMed 15240705PubMed 15507530PubMed 15659391PubMed 17125145Ref.4. Source: MGI

negative regulation of type 2 immune response

Inferred from genetic interaction PubMed 10438949. Source: MGI

positive regulation of B cell proliferation

Inferred from mutant phenotype PubMed 9171827. Source: MGI

positive regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of cellular component movement

Inferred from mutant phenotype PubMed 15860730. Source: MGI

protein import into nucleus, translocation

Inferred from electronic annotation. Source: Ensembl

protein localization

Inferred from mutant phenotype PubMed 15860730. Source: MGI

regulation of Rho GTPase activity

Inferred from mutant phenotype PubMed 15860730. Source: MGI

regulation of cell proliferation

Inferred from mutant phenotype PubMed 15240675. Source: MGI

regulation of inflammatory response

Inferred from mutant phenotype PubMed 9110977. Source: MGI

regulation of memory T cell differentiation

Inferred from mutant phenotype PubMed 15240675. Source: MGI

spermatogenesis

Inferred from mutant phenotype PubMed 11092811. Source: MGI

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

type 2 immune response

Inferred from mutant phenotype PubMed 9171827. Source: MGI

   Cellular_componentnucleus

Inferred from direct assay Ref.4. Source: MGI

replication fork

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionDNA binding

Inferred from direct assay PubMed 10490661PubMed 15611242PubMed 9110977. Source: MGI

chromatin DNA binding

Inferred from direct assay PubMed 17125145. Source: MGI

chromatin binding

Inferred from direct assay PubMed 12817026PubMed 15240705. Source: MGI

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 22406686. Source: IntAct

sequence-specific DNA binding

Inferred from direct assay PubMed 15659391. Source: MGI

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Tbx21Q9JKD83EBI-6253762,EBI-3863870

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 707707B-cell lymphoma 6 protein homolog
PRO_0000047099

Regions

Domain32 – 9968BTB
Zinc finger519 – 54224C2H2-type 1
Zinc finger547 – 56923C2H2-type 2
Zinc finger575 – 59723C2H2-type 3
Zinc finger603 – 62523C2H2-type 4
Zinc finger631 – 65323C2H2-type 5
Zinc finger659 – 68224C2H2-type 6
Region377 – 3804Required for interaction with NuRD complex and for transcriptional repressor activity

Amino acid modifications

Modified residue3341Phosphoserine; by MAPK1 By similarity
Modified residue3441Phosphoserine; by MAPK1 By similarity
Modified residue3801N6-acetyllysine; by EP300 By similarity

Experimental info

Mutagenesis211N → K: Abolishes interaction with NCOR2; mice have impaired GC formation and immunoglobulin affinity maturation with lower proliferation and survival of GC B-cells but normal differentiation of helper T-cell subsets and inflammatory response; in macrophages, no effect on transcriptional repression of genes encoding inflammatory molecules; when associated with A-116. In macrophages, no effect on competition with STAT5 for DNA-binding and transcriptional repression of genes encoding inflammatory molecules; when associated with A-116 and 377-Q--Q-380. Ref.11 Ref.12
Mutagenesis1161H → A: Abolishes interaction with NCOR2; mice have impaired GC formation and immunoglobulin affinity maturation with lower proliferation and survival of GC B-cells but normal differentiation of helper T-cell subsets and inflammatory response; in macrophages, no effect on transcriptional repression of genes encoding inflammatory molecules; when associated with K-21. In macrophages, no effect on competition with STAT5 for DNA-binding and transcriptional repression of genes encoding inflammatory molecules; when associated with K-21 and 377-Q--Q-380. Ref.11 Ref.12
Mutagenesis377 – 3804KKYK → QQYQ in macrophages, no effect on transcriptional repression of genes encoding inflammatory molecules. In macrophages, no effect on competition with STAT5 for DNA-binding and transcriptional repression of genes encoding inflammatory molecules; when associated with K-21 and A-116. Ref.12
Mutagenesis577 – 5804CNIC → GNIG in macrophages, inhibits competition with STAT5 for DNA-binding and abolishes transcriptional repression of genes encoding inflammatory molecules. Ref.12
Sequence conflict4561A → G in AAB17432. Ref.2

Sequences

Sequence LengthMass (Da)Tools
P41183 [UniParc].

Last modified February 1, 1995. Version 1.
Checksum: 2051DD808D32D5EC

FASTA70778,982
        10         20         30         40         50         60 
MASPADSCIQ FTRHASDVLL NLNRLRSRDI LTDVVIVVSR EQFRAHKTVL MACSGLFYSI 

        70         80         90        100        110        120 
FTDQLKCNLS VINLDPEISP EGFCILLDFM YTSRLNLREG NIMAVMTTAM YLQMEHVVDT 

       130        140        150        160        170        180 
CRKFIKASEA EMAPALKPPR EEFLNSRMLM PHDIMAYRGR EVVENNMPLR NTPGCESRAF 

       190        200        210        220        230        240 
APPLYSGLST PPASYPMYSH LPLSTFLFSD EELRDAPRMP VANPFPKERA LPCDSARQVP 

       250        260        270        280        290        300 
NEYSRPAMEV SPSLCHSNIY SPKEAVPEEA RSDIHYSVPE GPKPAVPSAR NAPYFPCDKA 

       310        320        330        340        350        360 
SKEEERPSSE DEIALHFEPP NAPLNRKGLV SPQSPQKSDC QPNSPTESCS SKNACILQAS 

       370        380        390        400        410        420 
GSPPAKSPTD PKACNWKKYK FIVLNSLNQN AKPEGSEQAE LGRLSPRAYP APPACQPPME 

       430        440        450        460        470        480 
PANLDLQSPT KLSASGEDST IPQASRLNNL VNRSLAGSPR SSSESHSPLY MHPPKCTSCG 

       490        500        510        520        530        540 
SQSPQHTEMC LHTAGPTFPE EMGETQSEYS DSSCENGTFF CNECDCRFSE EASLKRHTLQ 

       550        560        570        580        590        600 
THSDKPYKCD RCQASFRYKG NLASHKTVHT GEKPYRCNIC GAQFNRPANL KTHTRIHSGE 

       610        620        630        640        650        660 
KPYKCETCGA RFVQVAHLRA HVLIHTGEKP YPCEICGTRF RHLQTLKSHL RIHTGEKPYH 

       670        680        690        700 
CEKCNLHFRH KSQLRLHLRQ KHGAITNTKV QYRVSAADLP PELPKAC 

« Hide

References

« Hide 'large scale' references
[1]"The murine BCL6 gene is induced in activated lymphocytes as an immediate early gene."
Fukuda T., Miki T., Yoshida T., Hatano M., Ohashi K., Hirosawa S., Tokuhisa T.
Oncogene 11:1657-1663(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: BALB/c.
Tissue: Skeletal muscle.
[2]"BCL-6 expression during B-cell activation."
Allman D., Jain A., Dent A., Maile R.R., Selvaggi T., Kehry M.R., Staudt L.M.
Blood 87:5257-5268(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Muscle.
[3]"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].
Tissue: Olfactory epithelium.
[4]"BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor."
Okabe S., Fukuda T., Ishibashi K., Kojima S., Okada S., Hatano M., Ebara M., Saisho H., Tokuhisa T.
Mol. Cell. Biol. 18:4235-4244(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BCL6B.
[5]"Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene."
Davies J.M., Hawe N., Kabarowski J., Huang Q.-H., Zhu J., Brand N.J., Leprince D., Dhordain P., Cook M., Moriss-Kay G., Zelent A.
Oncogene 18:365-375(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZBTB7, SUBCELLULAR LOCATION.
[6]"BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control."
Shaffer A.L., Yu X., He Y., Boldrick J., Chan E.P., Staudt L.M.
Immunity 13:199-212(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS TRANSCRIPTIONAL REPRESSOR, DISRUPTION PHENOTYPE.
[7]"Role for Bcl-6 in the generation and maintenance of memory CD8+ T-cells."
Ichii H., Sakamoto A., Hatano M., Okada S., Toyama H., Taki S., Arima M., Kuroda Y., Tokuhisa T.
Nat. Immunol. 3:558-563(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MEMORY CD8(+) T-CELL MAINTENANCE, DISRUPTION PHENOTYPE.
[8]"Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells."
Phan R.T., Saito M., Kitagawa Y., Means A.R., Dalla-Favera R.
Nat. Immunol. 8:1132-1139(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[9]"BCL6 positively regulates AID and germinal center gene expression via repression of miR-155."
Basso K., Schneider C., Shen Q., Holmes A.B., Setty M., Leslie C., Dalla-Favera R.
J. Exp. Med. 209:2455-2465(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MIRNA REGULATION, TISSUE SPECIFICITY.
[10]"BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets."
Tiberi L., van den Ameele J., Dimidschstein J., Piccirilli J., Gall D., Herpoel A., Bilheu A., Bonnefont J., Iacovino M., Kyba M., Bouschet T., Vanderhaeghen P.
Nat. Neurosci. 15:1627-1635(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NEUROGENESIS, INTERACTION WITH NOTCH1 AND SIRT1, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE.
[11]"A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters."
Hatzi K., Jiang Y., Huang C., Garrett-Bakelman F., Gearhart M.D., Giannopoulou E.G., Zumbo P., Kirouac K., Bhaskara S., Polo J.M., Kormaksson M., Mackerell A.D. Jr., Xue F., Mason C.E., Hiebert S.W., Prive G.G., Cerchietti L., Bardwell V.J., Elemento O., Melnick A.
Cell Rep. 4:578-588(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ASN-21 AND HIS-116.
[12]"Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms."
Huang C., Hatzi K., Melnick A.
Nat. Immunol. 14:380-388(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN GERMINAL CENTER REACTIONS, DNA-BINDING, DOMAIN, INTERACTION WITH SMRT, DISRUPTION PHENOTYPE, MUTAGENESIS OF ASN-21; HIS-116; 377-LYS--LYS-380 AND 577-CYS--CYS-580.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D38377 mRNA. Translation: BAA07456.1.
U41465 mRNA. Translation: AAB17432.1.
BC052315 mRNA. Translation: AAH52315.1.
CCDSCCDS28082.1.
RefSeqNP_033874.1. NM_009744.3.
XP_006521785.1. XM_006521722.1.
UniGeneMm.347398.

3D structure databases

ProteinModelPortalP41183.
SMRP41183. Positions 5-129, 473-679.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198327. 4 interactions.
DIPDIP-59432N.
IntActP41183. 1 interaction.

PTM databases

PhosphoSiteP41183.

Proteomic databases

PRIDEP41183.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000023151; ENSMUSP00000023151; ENSMUSG00000022508.
GeneID12053.
KEGGmmu:12053.
UCSCuc007ytz.1. mouse.

Organism-specific databases

CTD604.
MGIMGI:107187. Bcl6.

Phylogenomic databases

eggNOGCOG5048.
HOGENOMHOG000001556.
HOVERGENHBG004831.
InParanoidP41183.
KOK15618.
OMANECDCRF.
OrthoDBEOG7KQ22S.
PhylomeDBP41183.
TreeFamTF330912.

Gene expression databases

ArrayExpressP41183.
BgeeP41183.
CleanExMM_BCL6.
GenevestigatorP41183.

Family and domain databases

Gene3D3.30.160.60. 5 hits.
3.30.710.10. 1 hit.
InterProIPR000210. BTB/POZ-like.
IPR011333. BTB/POZ_fold.
IPR013069. BTB_POZ.
IPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PfamPF00651. BTB. 1 hit.
[Graphical view]
SMARTSM00225. BTB. 1 hit.
SM00355. ZnF_C2H2. 6 hits.
[Graphical view]
SUPFAMSSF54695. SSF54695. 1 hit.
PROSITEPS50097. BTB. 1 hit.
PS00028. ZINC_FINGER_C2H2_1. 6 hits.
PS50157. ZINC_FINGER_C2H2_2. 6 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSBCL6. mouse.
NextBio280351.
PROP41183.
SOURCESearch...

Entry information

Entry nameBCL6_MOUSE
AccessionPrimary (citable) accession number: P41183
Secondary accession number(s): Q61065
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: July 9, 2014
This is version 126 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot