TCF/LEF family#History

{{See also|Response element|Enhanceosome}}

The discovery of the TCF/LEF genes as nuclear Wnt pathway components in the 90s{{cite journal |last1=Behrens |first1=J |last2=von Kries |first2=JP |last3=Kühl |first3=M |last4=Bruhn |first4=L |last5=Wedlich |first5=D |last6=Grosschedl |first6=R |last7=Birchmeier |first7=W |title=Functional interaction of beta-catenin with the transcription factor LEF-1. |journal=Nature |date=15 August 1996 |volume=382 |issue=6592 |pages=638–42 |doi=10.1038/382638a0 |pmid=8757136|bibcode=1996Natur.382..638B |s2cid=4369341 }}{{cite journal |last1=Huber |first1=O |last2=Korn |first2=R |last3=McLaughlin |first3=J |last4=Ohsugi |first4=M |last5=Herrmann |first5=BG |last6=Kemler |first6=R |title=Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. |journal=Mechanisms of Development |date=September 1996 |volume=59 |issue=1 |pages=3–10 |doi=10.1016/0925-4773(96)00597-7 |pmid=8892228|s2cid=14324471 |doi-access=free }} was a pivotal breakthrough for the Wnt signalling research field, plugging an important knowledge gap and enabling subsequent understanding of transcriptional regulation of Wnt target genes, particularly in embryonic development and cancer.

Before this discovery it was only known that upstream Wnt signalling mechanisms regulated the cytoplasmic abundance of the beta-catenin protein, which as a consequence translocated into the cell nucleus. However, since the protein structure of beta-catenin did not reveal any DNA-binding domain, it was still unclear how nuclear beta-catenin could regulate Wnt target genes.

{{anchor|Wnt response element}}Following the discovery, a model was established whereby Wnt signalling-regulated beta-catenin in the nucleus attaches to TCF/LEF DNA binding proteins, which recognise the DNA consensus sequence around the core 'CTTTG', called Wnt Response Element (WRE).{{cite journal |last1=Cadigan |first1=KM |last2=Waterman |first2=ML |title=TCF/LEFs and Wnt signaling in the nucleus. |journal=Cold Spring Harbor Perspectives in Biology |date=1 November 2012 |volume=4 |issue=11 |pages=a007906 |doi=10.1101/cshperspect.a007906 |pmid=23024173|pmc=3536346 }}

This rule that beta-catenin-TCF interaction on DNA regulates Wnt target gene expression, has nonetheless been broken by examples of Wnt- and beta-catenin-independent functions for TCF/LEF proteins (for instance in zebrafish CNS development{{cite journal |last1=Duncan |first1=RN |last2=Panahi |first2=S |last3=Piotrowski |first3=T |last4=Dorsky |first4=RI |title=Identification of Wnt Genes Expressed in Neural Progenitor Zones during Zebrafish Brain Development. |journal=PLOS ONE |date=2015 |volume=10 |issue=12 |pages=e0145810 |doi=10.1371/journal.pone.0145810 |pmid=26713625|pmc=4699909 |bibcode=2015PLoSO..1045810D |doi-access=free }}) and functional association of Wnt-regulated beta-catenin with other DNA-binding transcription factors such as SOX,{{cite journal |last1=Kormish |first1=JD |last2=Sinner |first2=D |last3=Zorn |first3=AM |title=Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. |journal=Developmental Dynamics |date=January 2010 |volume=239 |issue=1 |pages=56–68 |doi=10.1002/dvdy.22046 |pmid=19655378|pmc=3269784 }} FOXO,{{cite journal |last1=Essers |first1=MA |last2=de Vries-Smits |first2=LM |last3=Barker |first3=N |last4=Polderman |first4=PE |last5=Burgering |first5=BM |last6=Korswagen |first6=HC |title=Functional interaction between beta-catenin and FOXO in oxidative stress signaling. |journal=Science |date=20 May 2005 |volume=308 |issue=5725 |pages=1181–4 |doi=10.1126/science.1109083 |pmid=15905404|bibcode=2005Sci...308.1181E |s2cid=24572861 }} TBX.{{cite journal |last1=Zimmerli |first1=Dario |last2=Borrelli |first2=Costanza |last3=Jauregi-Miguel |first3=Amaia |last4=Söderholm |first4=Simon |last5=Brütsch |first5=Salome |last6=Doumpas |first6=Nikolaos |last7=Reichmuth |first7=Jan |last8=Murphy-Seiler |first8=Fabienne |last9=Aguet |first9=MIchel |last10=Basler |first10=Konrad |last11=Moor |first11=Andreas E |last12=Cantù |first12=Claudio |title=TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex |journal=eLife |date=18 August 2020 |volume=9 |doi=10.7554/eLife.58123|pmid=32808927 |pmc=7434441 |doi-access=free }} Then again, this beta-catenin-TCF interaction on DNA is now revealed as but the core of much larger protein complexes regulating transcription, called the Wnt enhanceosomes.{{cite journal |last1=Gammons |first1=M |last2=Bienz |first2=M |title=Multiprotein complexes governing Wnt signal transduction. |journal=Current Opinion in Cell Biology |date=April 2018 |volume=51 |pages=42–49 |doi=10.1016/j.ceb.2017.10.008 |pmid=29153704}} Conversely, additional mechanisms regulating TCF/LEF protein function have been discovered, such as phosphorylation{{cite journal |last1=Sokol |first1=SY |title=Wnt signaling through T-cell factor phosphorylation. |journal=Cell Research |date=July 2011 |volume=21 |issue=7 |pages=1002–12 |doi=10.1038/cr.2011.86 |pmid=21606952|pmc=3193496 }} and sumoylation.{{cite journal |last1=Yamamoto |first1=H |last2=Ihara |first2=M |last3=Matsuura |first3=Y |last4=Kikuchi |first4=A |title=Sumoylation is involved in beta-catenin-dependent activation of Tcf-4. |journal=The EMBO Journal |date=1 May 2003 |volume=22 |issue=9 |pages=2047–59 |doi=10.1093/emboj/cdg204 |pmid=12727872|pmc=156076 }}

The structure and function of TCF/LEF proteins explains this bimodal function. TCF/LEF genes encode proteins with an elaborate structure that can however be summarised by considering four main domains:

1. N-terminal domain: mediating interaction with beta-catenin, which is highly conserved and mediates the transcriptional activator function.
2. Control region: includes sequences regulating and mediating the transcriptional repressor function and encoding a transcriptional repressor binding domain for the Groucho family.
3. DNA-binding domain: includes a very highly conserved HMG (High Mobility Group) DNA-binding domain and the NLS (nuclear localisation sequence).
4. C-terminal tail: may contain an additional DNA-binding domain and an additional transcriptional repressor binding domain.{{cite book |last1=Hoppler |first1=Stefan |last2=Waterman |first2=Marian L. |chapter=Evolutionary Diversification of Vertebrate TCF/LEF Structure, Function, and Regulation |title=WNT Signaling in Development and Disease |date=2014 |pages=225–237 |doi=10.1002/9781118444122.ch17 |isbn=9781118444122 }}

Diversity in TCF/LEF protein structure and function comes from having different genes. Humans and jawed vertebrates generally have four genes encoding TCF/LEF proteins:

• TCF7 (also called TCF1)
• LEF1 (also called TCF1α)
• TCF7L1 (also called TCF3)
• TCF7L2 (also called TCF4)

Further diversity comes from expression from the same gene of alternative transcripts encoding different protein isoforms, particularly from the TCF7 and TCF7L2 genes:

• There are isoforms expressed from secondary promoters that encode proteins that lack the usual N-terminus and therefore specifically the beta-catenin binding domain (see above). These protein isoforms function not as bimodal transcription factors but as constitutive repressors, and they are refractory to upstream Wnt signalling regulation.{{cite journal |last1=Van de Wetering |first1=M |last2=Castrop |first2=J |last3=Korinek |first3=V |last4=Clevers |first4=H |title=Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties. |journal=Molecular and Cellular Biology |date=March 1996 |volume=16 |issue=3 |pages=745–52 |doi=10.1128/MCB.16.3.745 |pmid=8622675|pmc=231054 }}{{cite journal |last1=Hovanes |first1=K |last2=Li |first2=TW |last3=Munguia |first3=JE |last4=Truong |first4=T |last5=Milovanovic |first5=T |last6=Lawrence Marsh |first6=J |last7=Holcombe |first7=RF |last8=Waterman |first8=ML |title=Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. |journal=Nature Genetics |date=May 2001 |volume=28 |issue=1 |pages=53–7 |doi=10.1038/ng0501-53 |pmid=11326276|s2cid=28974522 }}
• There are isoforms from alternative splicing in the part of the transcript encoding the control region, which influence the propensity of the encoded protein isoforms to act as transcriptional repressors (without beta-catenin) or transcriptional activators (with beta-catenin).{{cite journal |last1=Liu |first1=F |last2=van den Broek |first2=O |last3=Destrée |first3=O |last4=Hoppler |first4=S |title=Distinct roles for Xenopus Tcf/Lef genes in mediating specific responses to Wnt/beta-catenin signalling in mesoderm development. |journal=Development |date=December 2005 |volume=132 |issue=24 |pages=5375–85 |doi=10.1242/dev.02152 |pmid=16291789|s2cid=20515922 |doi-access=free }}
• There are isoforms from alternative splicing in the part of the transcript encoding the C-terminal tail resulting in protein isoforms with and without the additional DNA-binding domain and resulting in changing the reading frame in which the last exon is translated with or without an additional transcriptional co-repressor binding domain.{{cite journal |last1=Atcha |first1=FA |last2=Syed |first2=A |last3=Wu |first3=B |last4=Hoverter |first4=NP |last5=Yokoyama |first5=NN |last6=Ting |first6=JH |last7=Munguia |first7=JE |last8=Mangalam |first8=HJ |last9=Marsh |first9=JL |last10=Waterman |first10=ML |title=A unique DNA binding domain converts T-cell factors into strong Wnt effectors. |journal=Molecular and Cellular Biology |date=December 2007 |volume=27 |issue=23 |pages=8352–63 |doi=10.1128/MCB.02132-06 |pmid=17893322|pmc=2169181 }}{{cite journal |last1=Ravindranath |first1=AJ |last2=Cadigan |first2=KM |title=The Role of the C-Clamp in Wnt-Related Colorectal Cancers. |journal=Cancers |date=3 August 2016 |volume=8 |issue=8 |page=74 |doi=10.3390/cancers8080074 |pmid=27527215|pmc=4999783 |doi-access=free }}

TCF/LEF proteins function as bimodal transcription factors:

• As described, TCF/LEF proteins act as transcriptional activators in association with nuclear beta-catenin (and transcriptional co-activators attached to beta-catenin);
• but without beta-catenin, TCF/LEF proteins function as transcriptional repressors (attached to transcriptional co-repressors members of the Groucho family).

Thus, as a consequence, Wnt target genes are actively repressed in the absence of Wnt signalling activity, then activated when Wnt signalling actively drives beta-catenin into the nucleus.{{cite journal |last1=Ramakrishnan |first1=AB |last2=Cadigan |first2=KM |title=Wnt target genes and where to find them. |journal=F1000Research |date=2017 |volume=6 |pages=746 |doi=10.12688/f1000research.11034.1 |pmid=28649368|pmc=5464219 |doi-access=free }}

TCF/LEF genes support diverse functions in embryonic development, stem cell biology, and in disease.{{cite journal |last1=Hoppler |first1=S |last2=Kavanagh |first2=CL |title=Wnt signalling: variety at the core. |journal=Journal of Cell Science |date=1 February 2007 |volume=120 |issue=Pt 3 |pages=385–93 |doi=10.1242/jcs.03363 |pmid=17251379|s2cid=30976795 |doi-access=free }}{{cite book |title=Wnt signaling in development and disease : molecular mechanisms and biological functions |date=2014 |location=Hoboken, New Jersey |isbn=9781118444122|last1=Hoppler |first1=Stefan |last2=Moon |first2=Randall T. }} Given the conservation of structure, functions of different TCF/LEF genes and proteins are often redundant in many organs and tissues where Wnt signalling is important, yet genetic analysis suggested from the beginning that this redundancy is only partial, suggesting TCF/LEF gene- and TCF isoform-specific functions, many of which are only now beginning to be discovered.

Prominent functions of TCF/LEF genes in embryonic development include vertebrate dorsal axis induction, anterior-posterior patterning of the developing Central Nervous System, neural crest development and many functions in organ development. Prominent functions of TCF/LEF genes in stem cell development have been particularly well dissected during the hair follicle cycle.{{cite journal |last1=DasGupta |first1=R |last2=Fuchs |first2=E |title=Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. |journal=Development |date=October 1999 |volume=126 |issue=20 |pages=4557–68 |doi=10.1242/dev.126.20.4557 |pmid=10498690}}{{cite journal |last1=Merrill |first1=BJ |last2=Gat |first2=U |last3=DasGupta |first3=R |last4=Fuchs |first4=E |title=Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. |journal=Genes & Development |date=1 July 2001 |volume=15 |issue=13 |pages=1688–705 |doi=10.1101/gad.891401 |pmid=11445543|pmc=312726 }} TCF/LEF genes have roles in many cancers, with their role in colorectal cancer possibly being the best understood.{{cite journal |last1=Mayer |first1=Claus-Dieter |last2=Magon de La Giclais |first2=Soizick |last3=Alsehly |first3=Fozan |last4=Hoppler |first4=Stefan |title=Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies |journal=Genes |date=May 2020 |volume=11 |issue=5 |pages=538 |doi=10.3390/genes11050538 |pmid=32403323 |pmc=7288467 |doi-access=free }} However, other human diseases have also been linked to TCF/LEF genes, particularly type 2 diabetes.{{cite journal |last1=Jin |first1=T |last2=Liu |first2=L |title=The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. |journal=Molecular Endocrinology |date=November 2008 |volume=22 |issue=11 |pages=2383–92 |doi=10.1210/me.2008-0135 |pmid=18599616|doi-access=free }}{{cite journal |last1=Chen |first1=X |last2=Ayala |first2=I |last3=Shannon |first3=C |last4=Fourcaudot |first4=M |last5=Acharya |first5=NK |last6=Jenkinson |first6=CP |last7=Heikkinen |first7=S |last8=Norton |first8=L |title=The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function. |journal=Diabetes |date=April 2018 |volume=67 |issue=4 |pages=554–568 |doi=10.2337/db17-0318 |pmid=29317436|pmc=5860863 }}

{{reflist}}

• NCBI CDD: [https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cd01388 cd01388] (SOX-TCF_HMG-box); [https://www.ebi.ac.uk/interpro/beta/entry/cdd/CD01388/protein/reviewed/taxonomy/uniprot/9606/ human proteins]

{{transcription factors|g4}}

{{DEFAULTSORT:TCF LEF family}}

Category:Developmental genes and proteins

Category:Transcription factors