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Transcription factor HES-4-B (Hairy and enhancer of split 4-B) (Protein hairy-2) (Xhairy2) (Protein hairy-2a) (Xhairy2b)

 HES4B_XENLA             Reviewed;         277 AA.
Q90VV1;
05-MAY-2009, integrated into UniProtKB/Swiss-Prot.
01-DEC-2001, sequence version 1.
28-MAR-2018, entry version 86.
RecName: Full=Transcription factor HES-4-B;
AltName: Full=Hairy and enhancer of split 4-B;
AltName: Full=Protein hairy-2;
Short=Xhairy2 {ECO:0000303|PubMed:17436284};
AltName: Full=Protein hairy-2a;
Short=Xhairy2b {ECO:0000303|PubMed:17724611};
Name=hes4-b;
Synonyms=hairy2 {ECO:0000303|PubMed:17436284},
hairy2b {ECO:0000303|PubMed:11703945};
Xenopus laevis (African clawed frog).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Amphibia; Batrachia; Anura; Pipoidea; Pipidae; Xenopodinae; Xenopus;
Xenopus.
NCBI_TaxID=8355;
[1] {ECO:0000305, ECO:0000312|EMBL:AAK63842.1}
NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
TISSUE=Tail bud {ECO:0000269|PubMed:11703945};
PubMed=11703945; DOI=10.1016/S1534-5807(01)00054-5;
Davis R.L., Turner D.L., Evans L.M., Kirschner M.W.;
"Molecular targets of vertebrate segmentation: two mechanisms control
segmental expression of Xenopus hairy2 during somite formation.";
Dev. Cell 1:553-565(2001).
[2] {ECO:0000312|EMBL:AAK39552.1}
NUCLEOTIDE SEQUENCE [MRNA].
Ishibashi S., Katamura M., Hashimoto C., Cho K.W.Y.;
"Involvement of hairy-related gene in organizer patterning.";
Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
[3] {ECO:0000312|EMBL:AAK39552.1}
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Kidney {ECO:0000312|EMBL:AAH70547.1};
NIH - Xenopus Gene Collection (XGC) project;
Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
[4] {ECO:0000305}
INTERACTION WITH HEY1.
PubMed=14648848; DOI=10.1002/dvdy.10406;
Van Wayenbergh R., Taelman V., Pichon B., Fischer A., Kricha S.,
Gessler M., Christophe D., Bellefroid E.J.;
"Identification of BOIP, a novel cDNA highly expressed during
spermatogenesis that encodes a protein interacting with the orange
domain of the hairy-related transcription factor HRT1/Hey1 in Xenopus
and mouse.";
Dev. Dyn. 228:716-725(2003).
[5] {ECO:0000305}
TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
PubMed=12774230; DOI=10.1007/s00427-003-0338-4;
Tsuji S., Cho K.W.Y., Hashimoto C.;
"Expression pattern of a basic helix-loop-helix transcription factor
Xhairy2b during Xenopus laevis development.";
Dev. Genes Evol. 213:407-411(2003).
[6] {ECO:0000305}
INTERACTION WITH HEY1, AND TISSUE SPECIFICITY.
PubMed=15531363; DOI=10.1016/j.ydbio.2004.08.019;
Taelman V., Van Wayenbergh R., Soelter M., Pichon B., Pieler T.,
Christophe D., Bellefroid E.J.;
"Sequences downstream of the bHLH domain of the Xenopus hairy-related
transcription factor-1 act as an extended dimerization domain that
contributes to the selection of the partners.";
Dev. Biol. 276:47-63(2004).
[7] {ECO:0000305}
FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
PubMed=16059909; DOI=10.1002/dvdy.20523;
Yamaguti M., Cho K.W.Y., Hashimoto C.;
"Xenopus hairy2b specifies anterior prechordal mesoderm identity
within Spemann's organizer.";
Dev. Dyn. 234:102-113(2005).
[8] {ECO:0000305}
FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
PubMed=16316406; DOI=10.1111/j.1440-169X.2005.00823.x;
Cui Y.;
"Hairy is a cell context signal controlling Notch activity.";
Dev. Growth Differ. 47:609-625(2005).
[9] {ECO:0000305}
TISSUE SPECIFICITY, AND INDUCTION.
PubMed=16818449; DOI=10.1242/dev.02458;
Taelman V., Van Campenhout C., Soelter M., Pieler T., Bellefroid E.J.;
"The Notch-effector HRT1 gene plays a role in glomerular development
and patterning of the Xenopus pronephros anlagen.";
Development 133:2961-2971(2006).
[10] {ECO:0000305}
FUNCTION, AND FUNCTION OF WRPW MOTIF.
PubMed=16586347; DOI=10.1387/ijdb.052106ym;
Murato Y., Yamaguti M., Katamura M., Cho K.W.Y., Hashimoto C.;
"Two modes of action by which Xenopus hairy2b establishes tissue
demarcation in the Spemann-Mangold organizer.";
Int. J. Dev. Biol. 50:463-471(2006).
[11] {ECO:0000305}
FUNCTION.
PubMed=17436284; DOI=10.1002/dvdy.21152;
Nagatomo K., Hashimoto C.;
"Xenopus hairy2 functions in neural crest formation by maintaining
cells in a mitotic and undifferentiated state.";
Dev. Dyn. 236:1475-1483(2007).
[12] {ECO:0000305}
FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
PubMed=17724611; DOI=10.1007/s00427-007-0176-x;
Murato Y., Nagatomo K., Yamaguti M., Hashimoto C.;
"Two alloalleles of Xenopus laevis hairy2 gene-evolution of duplicated
gene function from a developmental perspective.";
Dev. Genes Evol. 217:665-673(2007).
[13] {ECO:0000305}
FUNCTION, INTERACTION WITH ID3, INDUCTION, AND MUTAGENESIS OF
43-GLU--ARG-47.
PubMed=18721802; DOI=10.1016/j.ydbio.2008.08.003;
Nichane M., de Croze N., Ren X., Souopgui J., Monsoro-Burq A.H.,
Bellefroid E.J.;
"Hairy2-Id3 interactions play an essential role in Xenopus neural
crest progenitor specification.";
Dev. Biol. 322:355-367(2008).
[14] {ECO:0000305}
FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS OF 43-GLU--ARG-47.
PubMed=18710660; DOI=10.1016/j.ydbio.2008.07.026;
Nichane M., Ren X., Souopgui J., Bellefroid E.J.;
"Hairy2 functions through both DNA-binding and non DNA-binding
mechanisms at the neural plate border in Xenopus.";
Dev. Biol. 322:368-380(2008).
[15] {ECO:0000305}
FUNCTION, AND TISSUE SPECIFICITY.
PubMed=19253409; DOI=10.1002/dvdy.21883;
Murato Y., Hashimoto C.;
"Xhairy2 functions in Xenopus lens development by regulating p27(xic1)
expression.";
Dev. Dyn. 238:2179-2192(2009).
-!- FUNCTION: Transcriptional repressor. Binds DNA on N-box motifs:
5'-CACNAG-3'. Promotes floor plate development and prechordal
plate development. Required for lens development as early as the
stage of lens field formation, partly through regulation of gene
expression of the cell cycle inhibitor cdknx/p27(xic1). Required
for formation of the neural crest downstream of multiple signaling
pathways, and acts at the neural plate border via both DNA-binding
dependent and independent mechanisms; acts in a DNA-binding
dependent manner to repress pro-apoptotic and neural crest
differentiation genes, including id3, delta1, and cdknx/p27(xic1),
and thus promote the cell survival of neural plate border cells
and maintain them in an undifferentiated state. Represses
transcription of id3, at least in part through the repression of
bmp4. On the other hand, acts in a DNA-independent manner separate
from the transcriptional repressor function, to stimulate cell
proliferation and promote neural crest formation. Via this DNA-
independent route, acts in neurulae upstream of stat3 to
transiently up-regulate the notch ligand dll1/delta1, which in
turn up-regulates id3 expression. Then interacts directly with
id3, which blocks the transcriptional repressor function of hes4-
B/hairy2b to allow the progression of neural crest progenitors
through specification and differentiation. Also acts via
repressor-dependent and repressor-independent mechanisms in early
gastrulae to establish the prospective anterior prechordal
mesoderm identity in the Spemann organizer; induces specific genes
independently from direct transcriptional regulation, and
represses the genes specific for neighboring tissues through
direct transcriptional repression. Modulates lateral inhibition
during notch signaling and regulates the cell context dependent
effects of notch (which can have inhibitory, permissive or
enhancing roles in muscle or neural differentiation). Inhibits
myogenesis. {ECO:0000250|UniProtKB:Q90Z12,
ECO:0000269|PubMed:16059909, ECO:0000269|PubMed:16316406,
ECO:0000269|PubMed:16586347, ECO:0000269|PubMed:17436284,
ECO:0000269|PubMed:17724611, ECO:0000269|PubMed:18710660,
ECO:0000269|PubMed:18721802, ECO:0000269|PubMed:19253409}.
-!- SUBUNIT: Transcription repression requires formation of a complex
with a corepressor protein of the Groucho/TLE family. Interacts
with the bHLH protein hes6; this interaction may inhibit the
transcriptional repressor activity (By similarity). Binds DNA in
the form of a heterodimer with the bHLH protein hey1/hrt1.
Interacts (via Orange domain) with id3 (via HLH domain).
{ECO:0000250|UniProtKB:P14003, ECO:0000250|UniProtKB:Q90Z12,
ECO:0000269|PubMed:14648848, ECO:0000269|PubMed:15531363,
ECO:0000269|PubMed:18721802}.
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P14003,
ECO:0000255|PROSITE-ProRule:PRU00380, ECO:0000255|PROSITE-
ProRule:PRU00981}.
-!- TISSUE SPECIFICITY: Dynamically expressed in the borders of
several tissue territories. Expressed in the pre-placodal ectoderm
(PPE) from gastrula stage. During gastrulation, expressed in the
deep layer of the dorsal lip, the Spemann organizer and three
distinct regions in the prospective neuroectoderm: neural plate
border, presumptive floor plate/notoplate and anterior neural
plate. At later stages, expression is localized to the anterior of
the prechordal plate, the presomitic mesoderm, neural tube, neural
crest derivatives and several tissues of the central nervous
system, with expression in the developing floor plate continues to
at least the tadpole stage. From the early tailbud stage,
expressed in the dorsoanterior region of the developing
pronephros. During early tailbud stages, broadly expressed within
the pronephric mesoderm. and in the sensorial layer of the
ectoderm covering the pronephros anlagen. During late tailbud to
early tadpole stages, expressed in the ventral region of the
pronephros. Expression remains in the proximal and distal tubules
at late tadpole stages (stage 35). {ECO:0000269|PubMed:11703945,
ECO:0000269|PubMed:12774230, ECO:0000269|PubMed:15531363,
ECO:0000269|PubMed:16059909, ECO:0000269|PubMed:16316406,
ECO:0000269|PubMed:16818449, ECO:0000269|PubMed:17724611,
ECO:0000269|PubMed:18710660, ECO:0000269|PubMed:19253409}.
-!- DEVELOPMENTAL STAGE: Expressed zygotically. Shows higher zygotic
expression than hes4-A/hairy2a. {ECO:0000269|PubMed:12774230,
ECO:0000269|PubMed:17724611}.
-!- INDUCTION: By Notch-signaling. Acts in a complex regulatory loop
with other transcription factors and neural crest inducing signals
at the neural plate border. {ECO:0000269|PubMed:16059909,
ECO:0000269|PubMed:16316406, ECO:0000269|PubMed:16818449,
ECO:0000269|PubMed:18721802}.
-!- DOMAIN: Has a particular type of basic domain (presence of a
helix-interrupting proline) that binds to the N-box (CACNAG),
rather than the canonical E-box (CANNTG).
{ECO:0000250|UniProtKB:P14003}.
-!- DOMAIN: The C-terminal WRPW motif is a transcriptional repression
domain necessary for the interaction with Groucho/TLE family
members, transcriptional corepressors recruited to specific target
DNA by Hairy-related proteins (By similarity). The WPRW motif is
also required for the inductive function, independent of a
transcription regulation activity. {ECO:0000250|UniProtKB:P14003,
ECO:0000269|PubMed:16586347}.
-!- CAUTION: PubMed:17724611 reports that the probe used in
PubMed:12774230 cross-hybridizes with hes4-A/hairy2a, so the
maternal expression reported in PubMed:12774230 is in fact due to
hes4-A/hairy2a and not hes4-B/hairy2b. {ECO:0000305}.
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EMBL; AF383160; AAK63842.1; -; mRNA.
EMBL; BC070547; AAH70547.1; -; mRNA.
EMBL; AF356000; AAK39552.1; -; mRNA.
RefSeq; NP_001082161.1; NM_001088692.1.
UniGene; Xl.86822; -.
ProteinModelPortal; Q90VV1; -.
SMR; Q90VV1; -.
ELM; Q90VV1; -.
GeneID; 398258; -.
KEGG; xla:398258; -.
CTD; 398258; -.
Xenbase; XB-GENE-865740; hes4.
KO; K06054; -.
GO; GO:0005634; C:nucleus; ISS:UniProtKB.
GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
GO; GO:0043565; F:sequence-specific DNA binding; IPI:UniProtKB.
GO; GO:0008283; P:cell proliferation; IMP:UniProtKB.
GO; GO:0033504; P:floor plate development; IMP:UniProtKB.
GO; GO:0002088; P:lens development in camera-type eye; IMP:UniProtKB.
GO; GO:0007517; P:muscle organ development; IEA:UniProtKB-KW.
GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
GO; GO:0048642; P:negative regulation of skeletal muscle tissue development; IMP:UniProtKB.
GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB.
GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
GO; GO:0014029; P:neural crest formation; IMP:UniProtKB.
GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
GO; GO:0021501; P:prechordal plate formation; IMP:UniProtKB.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
CDD; cd00083; HLH; 1.
Gene3D; 4.10.280.10; -; 1.
InterPro; IPR011598; bHLH_dom.
InterPro; IPR036638; HLH_DNA-bd_sf.
InterPro; IPR003650; Orange_dom.
Pfam; PF07527; Hairy_orange; 1.
Pfam; PF00010; HLH; 1.
SMART; SM00353; HLH; 1.
SMART; SM00511; ORANGE; 1.
SUPFAM; SSF47459; SSF47459; 1.
PROSITE; PS50888; BHLH; 1.
PROSITE; PS51054; ORANGE; 1.
1: Evidence at protein level;
Developmental protein; Differentiation; DNA-binding; Myogenesis;
Neurogenesis; Notch signaling pathway; Nucleus; Repressor;
Transcription; Transcription regulation.
CHAIN 1 277 Transcription factor HES-4-B.
/FTId=PRO_0000371246.
DOMAIN 34 91 bHLH. {ECO:0000255|PROSITE-
ProRule:PRU00981}.
DOMAIN 110 143 Orange. {ECO:0000255|PROSITE-
ProRule:PRU00380}.
MOTIF 274 277 WRPW motif. {ECO:0000255}.
MUTAGEN 43 47 EKRRR->RELEE: Disrupts DNA-binding.
Unable to repress id3 transcription.
Disrupts the ability to promote cell
survival and up-regulate neural border
genes. Does not disrupt the ability to
promote cell proliferation and neural
crest cell formation.
{ECO:0000269|PubMed:18710660,
ECO:0000269|PubMed:18721802}.
SEQUENCE 277 AA; 29825 MW; F46C357B23484040 CRC64;
MPADSMEKPT ASPIAGAPAN SAQTPDKPKS ASEHRKSSKP IMEKRRRARI NESLGQLKTL
ILDALKKDSS RHSKLEKADI LEMTVKHLRN LQRVQMTAAL TADPSVLGKY RAGFNECMNE
VTRFLSTCEG VNTEVRTRLL GHLSSCLGQI VAMNYQQPPS SQQPVHVQLP SSTPVPMPCK
VNPAEAISPK VFQGGFQLVP ATDGQFAFLI PNPAYTSSPG PVIPLYANAT SPGGPPSQSP
VQGLTSFAHK MPHMAQAVSP LGGSTRADSA ESVWRPW


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