POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation (Homo sapiens)

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11, 21, 24, 30, 32...11, 14, 19, 21, 408, 11, 13, 16, 19...11, 14, 15, 19, 21...2, 6, 7, 9-11, 19...11, 14, 19, 215, 11, 19, 21, 31...11, 14, 21, 313, 11, 12, 18, 19, 21...11, 14, 15, 19, 21...1, 19, 21, 22, 26...11, 14, 19, 21, 36...4, 11, 17, 21, 27...nucleoplasmcytosolPOLR2D POLR2E POLR2A POLR2H POU5F1 NANOG POLR2L POLR2K POU5F1:SOX2:NANOG:EPHA1 genePOLR2G SOX2POLR2I POU5F1 POLR2A POLR2I SOX2 POLR2L POLR2G RNA Polymerase IIholoenzyme complex(generic)POU5F1POU5F1:SOX2:NANOG:FGF2 genePOLR2F NR6A1-1 RNA Polymerase IIholoenzyme complex(generic)RNA Polymerase IIholoenzyme complex(generic)POLR2K POLR2D RNA Polymerase IIholoenzyme complex(generic)POLR2H NANOGZIC3POLR2B EPHA1 gene POLR2F POLR2D SOX2 POLR2K POLR2C NANOG POLR2H POLR2I POLR2B POLR2E POU5F1 N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188)POLR2D FGF2(10-155)POLR2F NANOG SOX2 POLR2J POLR2I NR6A1(GCNF):TDGF1geneEPHA1POLR2J POLR2I EPHA1 genePOLR2A STAT3 geneFGF2 genePOU5F1:SOX2:NANOG:STAT3 genePOLR2L POLR2H POLR2G STAT3 gene POLR2G POLR2B POLR2J POLR2E ZIC3 gene POLR2J POLR2E NANOG POLR2K POU5F1:SOX2:NANOG:ZIC3 genePOLR2C FOXD3 genePOLR2B POU5F1:SOX2:NANOG:FOXD3 genePOLR2B ZIC3 genePOLR2A POLR2G FOXD3 gene POU5F1 POLR2E SOX2 POLR2L POLR2E POLR2J POLR2K NANOG POLR2I STAT3TDGF1 gene POLR2C POLR2A POLR2A POLR2F POLR2K POLR2F POU5F1 NANOG POLR2H POU5F1 POLR2G POU5F1:SOX2:NANOG:TDGF1 genePOLR2L POLR2H FOXD3TDGF1 gene POLR2C SOX2 POLR2B POLR2D RNA Polymerase IIholoenzyme complex(generic)POLR2C POLR2D TDGF1 geneSOX2 POLR2L POLR2F FGF2 gene POLR2C POLR2J RNA Polymerase IIholoenzyme complex(generic)714, 15, 21, 31, 40...14, 21, 4014, 15, 2114, 21, 40, 42, 4314, 2114, 15, 21


Description

POU5F1 (OCT4), SOX2, and NANOG bind elements in the promoters of target genes. The target genes of each transcription factor overlap extensively: POU5F1, SOX2, and NANOG co-occupy at least 353 genes (Boyer et al. 2005). About half of POU5F1 targets also bind SOX2 and about 90% of these also bind NANOG (Boyer et al. 2005). Upon binding the transcription factors activate expression of one subset of target genes and repress another subset (Kim et al. 2006, Matoba et al. 2006, Player et al. 2006, Babaie et al. 2007). The targets listed in this module are those that have been described as composing activated genes in the core transcriptional network of pluripotent stem cells (Assou et al. 2007, Chavez et al. 2009, Jung et al. 2010). Inferences from mouse to human have been made with caution because of significant differences between the two species (Ginis et al. 2004). View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114884view16:39, 25 January 2021ReactomeTeamReactome version 75
113330view11:40, 2 November 2020ReactomeTeamReactome version 74
112542view15:50, 9 October 2020ReactomeTeamReactome version 73
101455view11:32, 1 November 2018ReactomeTeamreactome version 66
100993view21:11, 31 October 2018ReactomeTeamreactome version 65
100529view19:45, 31 October 2018ReactomeTeamreactome version 64
100076view16:28, 31 October 2018ReactomeTeamreactome version 63
99627view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99233view12:44, 31 October 2018ReactomeTeamreactome version 62
93996view13:50, 16 August 2017ReactomeTeamreactome version 61
93605view11:28, 9 August 2017ReactomeTeamreactome version 61
88106view09:56, 26 July 2016RyanmillerOntology Term : 'transcription pathway' added !
88105view09:53, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86712view09:24, 11 July 2016ReactomeTeamreactome version 56
83109view09:59, 18 November 2015ReactomeTeamVersion54
81441view12:58, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
EPHA1 gene ProteinENSG00000146904 (Ensembl)
EPHA1 geneGeneProductENSG00000146904 (Ensembl)
EPHA1ProteinP21709 (Uniprot-TrEMBL)
FGF2 gene ProteinENSG00000138685 (Ensembl)
FGF2 geneGeneProductENSG00000138685 (Ensembl)
FGF2(10-155)ProteinP09038 (Uniprot-TrEMBL)
FOXD3 gene ProteinENSG00000187140 (Ensembl)
FOXD3 geneGeneProductENSG00000187140 (Ensembl)
FOXD3ProteinQ9UJU5 (Uniprot-TrEMBL)
N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188)ProteinP13385 (Uniprot-TrEMBL)
NANOG ProteinQ9H9S0 (Uniprot-TrEMBL)
NANOGProteinQ9H9S0 (Uniprot-TrEMBL)
NR6A1(GCNF):TDGF1 geneComplexR-HSA-2892230 (Reactome)
NR6A1-1 ProteinQ15406-1 (Uniprot-TrEMBL)
POLR2A ProteinP24928 (Uniprot-TrEMBL)
POLR2B ProteinP30876 (Uniprot-TrEMBL)
POLR2C ProteinP19387 (Uniprot-TrEMBL)
POLR2D ProteinO15514 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2G ProteinP62487 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2I ProteinP36954 (Uniprot-TrEMBL)
POLR2J ProteinP52435 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
POU5F1 ProteinQ01860 (Uniprot-TrEMBL)
POU5F1:SOX2:NANOG:EPHA1 geneComplexR-HSA-2889014 (Reactome)
POU5F1:SOX2:NANOG:FGF2 geneComplexR-HSA-2889015 (Reactome)
POU5F1:SOX2:NANOG:FOXD3 geneComplexR-HSA-2889032 (Reactome)
POU5F1:SOX2:NANOG:STAT3 geneComplexR-HSA-2889003 (Reactome)
POU5F1:SOX2:NANOG:TDGF1 geneComplexR-HSA-2889018 (Reactome)
POU5F1:SOX2:NANOG:ZIC3 geneComplexR-HSA-2889030 (Reactome)
POU5F1ProteinQ01860 (Uniprot-TrEMBL)
RNA Polymerase II

holoenzyme complex

(generic)		ComplexR-HSA-209680 (Reactome)
SOX2 ProteinP48431 (Uniprot-TrEMBL)
SOX2ProteinP48431 (Uniprot-TrEMBL)
STAT3 gene ProteinENSG00000168610 (Ensembl)
STAT3 geneGeneProductENSG00000168610 (Ensembl)
STAT3ProteinP40763 (Uniprot-TrEMBL)
TDGF1 gene ProteinENSG00000241186 (Ensembl)
TDGF1 geneGeneProductENSG00000241186 (Ensembl)
ZIC3 gene ProteinENSG00000156925 (Ensembl)
ZIC3 geneGeneProductENSG00000156925 (Ensembl)
ZIC3ProteinO60481 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
EPHA1 geneR-HSA-2972967 (Reactome)
EPHA1 geneR-HSA-480509 (Reactome)
EPHA1ArrowR-HSA-480509 (Reactome)
FGF2 geneR-HSA-2972960 (Reactome)
FGF2 geneR-HSA-480515 (Reactome)
FGF2(10-155)ArrowR-HSA-480515 (Reactome)
FOXD3 geneR-HSA-2972964 (Reactome)
FOXD3 geneR-HSA-452750 (Reactome)
FOXD3ArrowR-HSA-452750 (Reactome)
N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188)ArrowR-HSA-452338 (Reactome)
NANOGR-HSA-2972956 (Reactome)
NANOGR-HSA-2972960 (Reactome)
NANOGR-HSA-2972962 (Reactome)
NANOGR-HSA-2972964 (Reactome)
NANOGR-HSA-2972967 (Reactome)
NANOGR-HSA-2972978 (Reactome)
NR6A1(GCNF):TDGF1 geneTBarR-HSA-452338 (Reactome)
POU5F1:SOX2:NANOG:EPHA1 geneArrowR-HSA-2972967 (Reactome)
POU5F1:SOX2:NANOG:EPHA1 geneArrowR-HSA-480509 (Reactome)
POU5F1:SOX2:NANOG:FGF2 geneArrowR-HSA-2972960 (Reactome)
POU5F1:SOX2:NANOG:FGF2 geneArrowR-HSA-480515 (Reactome)
POU5F1:SOX2:NANOG:FOXD3 geneArrowR-HSA-2972964 (Reactome)
POU5F1:SOX2:NANOG:FOXD3 geneArrowR-HSA-452750 (Reactome)
POU5F1:SOX2:NANOG:STAT3 geneArrowR-HSA-2972956 (Reactome)
POU5F1:SOX2:NANOG:STAT3 geneArrowR-HSA-452515 (Reactome)
POU5F1:SOX2:NANOG:TDGF1 geneArrowR-HSA-2972962 (Reactome)
POU5F1:SOX2:NANOG:TDGF1 geneArrowR-HSA-452338 (Reactome)
POU5F1:SOX2:NANOG:ZIC3 geneArrowR-HSA-2972978 (Reactome)
POU5F1:SOX2:NANOG:ZIC3 geneArrowR-HSA-480470 (Reactome)
POU5F1R-HSA-2972956 (Reactome)
POU5F1R-HSA-2972960 (Reactome)
POU5F1R-HSA-2972962 (Reactome)
POU5F1R-HSA-2972964 (Reactome)
POU5F1R-HSA-2972967 (Reactome)
POU5F1R-HSA-2972978 (Reactome)
R-HSA-2972956 (Reactome) The STAT3 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Lister et al. 2009, Jung et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007) activate expression.
R-HSA-2972960 (Reactome) The FGF2 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005), SOX2 (Boyer et al. 2005, Lister et al. 2009), NANOG (Boyer et al. 2005, Lister et al. 2009) and expression of the FGF2 mRNA is activated by POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007).
R-HSA-2972962 (Reactome) The TDGF1 (CRIPTO) gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Tantin et al. 2008, Jung et al. 2010, Watanabe et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009, Watanabe et al. 2010). POU5F1 (Babaie et al. 2007, Greber et al. 2007, Watanabe et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007, Watanabe et al. 2010) activate expression. Embryonal carcinoma cells that express higher levels of TDGF1 are more tumorigenic (Watanabe et al. 2010).
R-HSA-2972964 (Reactome) The FOXD3 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jung et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 activates expression (Babaie et al. 2007, Kunarso et al. 2010).
R-HSA-2972967 (Reactome) The EPHA1 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Jung et al. 2010, Kunarso et al. 2010, Goke et al. 2011), SOX2 (Boyer et al. 2005, Lister et al. 2009), NANOG (Boyer et al. 2005, Lister et al. 2009, Kunarso et al. 2010) and expression of the EPHA1 mRNA is activated by POU5F1 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007).
R-HSA-2972978 (Reactome) POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the ZIC3 gene (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) activate expression. In mouse, Zic3 binds the Nanog promoter and activates transcription, thus forming a positive feedback loop (Lim et al. 2010).
R-HSA-452338 (Reactome) The TDGF1 (CRIPTO) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. TDGF1/CRIPTO is expressed in embryonic stem cells (Adewumi et al. 2007, Li et al. 2006, Assou et al. 2009). GCNF (NR6A1) binds to the promoter of the TDGF1 (CRIPTO) gene and downregulates expression of TDGF1 (CRIPTO) during differentiation (Hentschke et al. 2006). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the TDGF1 gene and enhance transcription (Babaie et al. 2007, Greber et al. 2007, Watanabe et al. 2010). SOX2 binds the TDGF1 promoter adjacent to POU5F1 (Boyer et al. 2005). TDGF1 is a marker of undifferentiated stem cells (reviewed in Bianco et al. 2010, de Castro et al. 2010). Expression of TDGF1 is associated with tumorigenesis (Ciardiello et al. 1991).
R-HSA-452515 (Reactome) The STAT3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. STAT3 is expressed in embryonic stem cells (Schuringa et al. 2002, Fong et al. 2008). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the STAT3 gene and enhance transcription (Boyer et al. 2005, Greber et al. 2007, Fong et al. 2008). The binding site of POU5F1 is adjacent to the binding site of SOX2 in the STAT3 promoter (Boyer et al. 2005). Signaling by LIF via STAT3 in murine but not human stem cells is sufficient to prevent differentiation (Schuringa et al. 2002, Humphrey et al. 2004, Daheron et al. 2004).
R-HSA-452750 (Reactome) The Forkhead box protein D3 (FOXD3) gene is transcribed and translated to yield FOXD3 protein. FOXD3 is expressed in blastomeres of the inner cell mass (Galan et al. 2010, Arduini et al. 2012). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the FOXD3 gene and POU5F1 enhances transcription (Babaie et al. 2007, Kunarso et al. 2010). The binding site of POU5F1 is not adjacent to the binding site of SOX2 on the FOXD3 promoter (Boyer et al. 2005). FOXD3 is a molecular marker of stem cells (Calloni et al.2013) and a balance of FOXD3 expression is required to maintain pluripotency (Arduini and Brinvalou 2012, inferred from mouse in Liu and Labosky 2008).
R-HSA-480470 (Reactome) The ZIC3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the ZIC3 gene and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) enhances transcription. SOX2 binds adjacent to POU5F1 on the ZIC3 promoter (Boyer et al. 2005). ZIC3 is expressed in embryonic stem cells where it maintains pluripotency (Lim et al. 2007). As inferred from mouse, ZIC3 is involved in correct patterning during gastrulation (Ware et al. 2006) and mutations in ZIC3 cause heterotaxy in humans (Gebbia et al. 1997, Ware et al. 2004).
R-HSA-480509 (Reactome) The EPHA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. EPHA1 is expressed most highly in epidermis of skin and is downregulated in nonmelanomal skin cancers (Hafner et al. 2006). EPHA1 is expressed at lower levels in liver, colon, small intestine, bladder, kidney, prostate, and thymus (Hafner et al. 2006). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the EPHA1 gene and OCT4 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007) and NANOG (Greber et al. 2007) enhance transcription. The binding site of POU5F1 is adjacent to the binding site of SOX2 on the promoter of EPHA1 (Boyer et al. 2005). Expression and kinase activity of EPHA1 correlate with maintenance of pluripotency (Son et al. 2013).
R-HSA-480515 (Reactome) The FGF2 (bFGF) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. FGF2 is expressed in most tissues including kidney, skin, liver, ureter, and vasculature (Hughes and Hall 1993). FGF2 is expressed in about 35% of tumor lines (Chandler et al. 1999). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the FGF2 gene and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) enhance transcription. The binding site of POU5F1 is adjacent to the binding site of SOX2 on the FGF2 promoter (Boyer et al. 2005). FGF2 maintains human embryonic stem cells in an undifferentiated state (Dvorak et al. 2005, Eiselleova et al. 2009).
RNA Polymerase II

holoenzyme complex

(generic)		mim-catalysisR-HSA-452338 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)		mim-catalysisR-HSA-452515 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)		mim-catalysisR-HSA-452750 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)		mim-catalysisR-HSA-480470 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)		mim-catalysisR-HSA-480509 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)		mim-catalysisR-HSA-480515 (Reactome)
SOX2R-HSA-2972956 (Reactome)
SOX2R-HSA-2972960 (Reactome)
SOX2R-HSA-2972962 (Reactome)
SOX2R-HSA-2972964 (Reactome)
SOX2R-HSA-2972967 (Reactome)
SOX2R-HSA-2972978 (Reactome)
STAT3 geneR-HSA-2972956 (Reactome)
STAT3 geneR-HSA-452515 (Reactome)
STAT3ArrowR-HSA-452515 (Reactome)
TDGF1 geneR-HSA-2972962 (Reactome)
TDGF1 geneR-HSA-452338 (Reactome)
ZIC3 geneR-HSA-2972978 (Reactome)
ZIC3 geneR-HSA-480470 (Reactome)
ZIC3ArrowR-HSA-480470 (Reactome)
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