SNAI1

Protein SNAI1

Identifiers
snail homolog 1
HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863, GENECARDS:GC20P048599
snail homolog 1 (Drosophila)
HUGO:SNAI1, HGNC:11128, ENTREZ:6615, UNIPROT:O95863
"snail 1 (drosophila homolog), zinc finger protein"
HUGO:SNAI1 HGNC:11128 ENTREZ:6615 UNIPROT:O95863 GENECARDS:SNAI1 KEGG:6615 ATLASONC:SNAI1ID452ch20q13 WIKI:SNAI1

Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
EMT Senescence / SENESCENCE
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / WNT_NON_CANONICAL

References
Feedback loops
PMID:22514743
PMID:17018611
Snai1, Snai2, E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion.
PMID:17563753
Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition.
PARP1 poly(ADP)ribosylates SNAI1 and activates it and EMT program
PMID:21577210

SNAI1@Nucleus

References
em_emtc_emtc_re8( EMT Senescence ):
PMID:16001073
RAC1B increases the cellular level of ROS, causing an upregulation of Snail rexpression and induction of EMT
PMID:17563753
Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition.
em_emtc_emtc_re1( EMT Senescence ):
PMID:20731704
PMID:21317430
In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6???8 h.
Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation
PMID:22406545
TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways
PMID:16617148
Negative feedback by SNAI1 itself
PMID:17671186
KLF8 directly bound to the promotor of Snail and repressed Snail expression
Snail promoter is regulated positively by NFkB_p65
PMID:16831886
PMID:18832382
HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression.
HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter.
Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1
HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression
em_emtc_emtc_re2( EMT Senescence ):
PMID:14623871
Activation of Slug (SNAI2) by two mechanisms:
-transcriptional activation of Slug by the CTNNB1and TCF/LEF complex
-activation of the ERK pathway.
When adherens junctions are established in dense cultures, ErbB1/2 and the ERK pathway become inactive, CTNNB1 is localized at adherens junctions, Slug expression is reduced, and E-cadherin transcription is induced.
Antibody-mediated disruption of adherens junctions led to nuclear CTNNB1 localization and enhanced beta-catenin signaling, induction of Slug and inhibition of E-cadherin expression.
PMID:17093497
PMID:12490555
Snail1 induces Snail2 transcription.
Snail is able to induce the expression of Slug and all other neural crest markers (Zic5, FoxD3, Twist and Ets1)
PMID:16510505
Snail2 activates the Snail2 promoter
PMID:21199805
Twist1 binds to an E-box on the proximate Snail2 promoter to induce its transcription.
PMID:17550342
Activation of KIT by binding to KITLG induces SNAI2 expression
em_emtc_emtc_re4( EMT Senescence ):
PMID:19208835
TCF8 (ZEB1) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator.
Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction
em_emtc_emtc_re6( EMT Senescence ):
PMID:21883379
PMID:18297062
TWIST is a downstream target of HIF-1
Hypoxia or HIF-1 induces EMT through the direct activation of TWIST expression
PMID:19412634
Twist is a target of Snail1
PMID:22945800
Expression of Twist1 and Snail1 are mutually dependent
Knock-down of Snail1 downregulates Twist1 protein and mRNA
Knock- down of Twist1 interferes with TGFb-mediated induction of Snail1.
PMID:22006115
Alternatively, it has also been reported that Snail1 transcriptionally represses Twist1
PMID:17403902
Twist1 is a direct downstream target of NKFB.
em_emtc_emtc_re26( EMT Senescence ):
PMID:21051859
TCF3 (E47) is upregulated by Snail1, Snail2, Zeb1.
em_emtc_emtc_re36( EMT Senescence ):
PMID:12668723
Snail binds directly to the E-boxes of the promoters of claudin et occludin genes, resulting in complete repression of their promoter activity
em_emtc_emtc_re65( EMT Senescence ):
PMID:10048576
The gene expressions of MMP-1, MMP-3, and MMP-9 and gelatinolytic activity of MMP-9 were significantly increased in high ETS-1 expression cells.
Low ETS-1 expression cells could not spread on a vitronectin substratum, and the phosphorylation of focal adhesion kinase was markedly impaired because of the reduced expression of integrin b3
PMID:16079281
MMP-9 transcription is activated in response to Snail expression
Oncogenic H-Ras (RasV12) synergistically co-operates with Snail in the induction of MMP-9 transcription and expression.
Phosphorylated Sp-1 is recruited to the MMP-9 promoter following activation of the Erk1/2 pathway
PMID:19564415
The transcription factor FOXO3, negatively regulated by binding to 14-3-3 protein family, induces MMP9 and MMP13 expression.
This explains the role of FOXO3 in promoting tumor invasion.
PMID:22439866
c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1.
PMID:8844971
Molecular mechanism of transcriptional activation of human gelatinase B (=MMP9) by proximal promoter. (NFKB)
PMID:16556862
ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups
em_emtc_emtc_re235( EMT Senescence ):
PMID:19597490
SMAD3 and SMAD4 interact and form a complex with SNAIL1
em_emtc_emtc_re275( EMT Senescence ):
PMID:9618481
-Smad4 transactivated the proximal p21 promoter 1.3-fold
-Smad2 transactivated the proximal p21 promoter 3-fold
-Smad2/4 transactivated the proximal p21 promoter 12-fold
-Smad3 transactivated the proximal p21 promoter 25-fold
-Smad3/Smad2 transactivated the proximal p21 promoter 40-fold
-Smad3/Smad4 transactivated the proximal p21 promoter 110-fold
-Smad2/Smad3/Smad4 transactivated the proximal p21 promoter 140-fold
Smad proteins act as Transcriptional Activators via functional interactions with the Transcription factor Sp1
PMID:12545156
Myc represses differentiation-induced p21 expression via Miz-1-dependent interaction with the p21 core promoter
Myc binds the p21 core promoter in vitro through interaction with Miz-1
Myc and Miz-1 interact with the p21 promoter in vivo
PMID:15155580
Snail regulates cell-cycle progression and survival:
Snail regulates components of the early to late G1 transition and the G1/S checkpoint.
Snail represses Cyclin D2 transcription and increases p21/Cip1 transcription.
SNAI2 induces p21CIP1 (CDKN1A) expression
PMID:23869868
PMID:23140366
p53 transactivate p21
PMID:11283614
Myc: an ubiquitous mediator of cell growth and proliferation
Myc can both activate and repress transcription, depending on the nature of associated factors
TGFB downregulates Myc to cause cell cycle arrest.
TGFB activates p15INK4B and/or p21CIP1 (inhibitor of CDKs) ==> CDK inhibition by TGFB
TGFB downregulates cdc25A (a phosphatase, activator of CDKs) ==> CDK inhibition by TGFB
PMID:2191300
Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter.
PMID??:28536364
c-myc is transcriptionally upregulated by NF-??B
PMID:20027199
MYC induces DNA damage throuh an increase in ROS production, innapropriate DNA synthesis and abrogation of DNA repair
PMID:20713526
MYC supress the activity of anti-apoptotic BCL2 and BCLXL (BCL2L1) genes
PMID??:20713526
MYC in complex with CDK2 alone inhibit senescence through the inhibition of p16 and p21 expression as well as TERT and BMI1 expression increase. MYC in complex with CDK2 and p27KIP1 induces senescence through the expression increase of p16 and p21 as well as TERT and BMI1 expression decrease. WRN inhibit MYC induced senescence.
PMID??: PMID:17055429
MYC stimulate P53 and ARF
em_emtc_emtc_re353( EMT Senescence ):
PMID:9157999
VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold.
Protein levels were shown to increase concordantly.
PMID:15111329
VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is PKC/ERK pathway-dependent.
Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases
PMID:16716598
PMID:11708773
Endothelin1 is target gene of HIF1
PMID:21041997
In cells induced to undergo EMT, TGFB also activates the expresion of ZEB1 and ZEB2 through upregulation of ETS1 expression, which then may cooperate with the bHLH transcription factor E47 (TCF3)
PMID:17615296
TGFB induces ETS1 transcriptional expression.
TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457)
ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1.
Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3)
em_emtc_emtc_re355( EMT Senescence ):
Snail1 induces the nuclear translocation of Ets1, another factor required for Zeb1 expression.
Both Twist and Ets1 bind to the ZEB1 promoter although to different elements: whereas Ets1 interacts with the proximal promoter, Twist does it with a 700-bp sequence upstream of the transcription start site.
em_emtc_emtc_re356( EMT Senescence ):
PMID:22286765
Six1 induces ZEB1 and EMT through transcriptional repression of miR200.
PMID:20706219
Feedback loop between ZEB1, ZEB2 and MIR200 family
PMID:19935649
ZEB1 inhibits expression of MIR200 family
PMID:22514743
SNAI1 represses expression of all MIR200 family members.
em_emtc_emtc_re366( EMT Senescence ):
SNAI1 inhibits miR-203
SNAI1 represses miR-203 and miR-200b expression
PMID:21159887
p53 activates expression of miR-203
PMID:20702634
Feedback loop: ZEB1 inhibits expression of MIR203 and MIR183
ZEB1 directly controls transcription of the miR-203 and miR-183 and miR-200 family genes
ZEB2 inhibits expression of MIR203
em_emtc_emtc_re454( EMT Senescence ):
PMID:15459715
PMID:15448698
Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT.
Snail is highly unstable, with a short half-life about 25 min.
GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein.
Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization.
A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT
Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo
Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT.
em_emtc_emtc_re523( EMT Senescence ):
PMID:16232121
Snail and Slug bind to the E-box motifs present in the human Claudin-1 promoter.
High levels of Snail and Slug correlatedwith lowlevels of Claudin-1 expression.
It is proposed that Claudin-1 is a direct downstream target gene of Snail family factors in epithelial cells
PMID:15151915
The transcription factors B-catenin/Tcf complex has been shown to bind directly to the claudin-1 and claudin-2 promoters.
SNAI2 represses Claudin-1 expression
SNAI1 represses Claudin-1 expression
em_emtc_emtc_re721( EMT Senescence ):
PMID:18172008
p53 induces PTEN transcription
Snai1 inhibits gene expression
em_emtc_emtc_re1184( EMT Senescence ):
PMID:22796940
Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2.
PMID:14673164
Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity.
Interaction between Snail, HDAC1 and HDAC2, and the corepressor Sin3A is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression.
em_emtc_emtc_re1185( EMT Senescence ):
PMID:21685935
EZH2 supports carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1 and HDAC2 and Snail to inhibit E-cadherin.
em_emtc_emtc_re1222( EMT Senescence ):
PMID:17537911
Ectopic expression of any one of (Twist, Snail, or Goosecoid) led to induction of both FOXC2 mRNA and protein expression.
em_emtc_emtc_re1225( EMT Senescence ):
PMID:17490644
Snai1 and TCF3 (E47) upregulate both mRNA and protein level of ID1
This upregulation depends on SP1 or AP1 co-transcription factors
Erk contributes to the recruitment or assembly of proteins to Id-1 promoter

SNAI1|pho@Nucleus

References
em_emtc_emtc_re454( EMT Senescence ):
PMID:15459715
PMID:15448698
Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT.
Snail is highly unstable, with a short half-life about 25 min.
GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein.
Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization.
A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT
Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo
Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT.

SNAI1|pho|pho@Cytosol

References
em_emtc_emtc_re455( EMT Senescence ):
PMID:15459715
PMID:15448698
Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT.
Snail is highly unstable, with a short half-life about 25 min.
GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein.
Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization.
A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT
Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo
Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT.
em_emtc_emtc_re456( EMT Senescence ):
PMID:19411070
TNFa dramatically enhanced the protein stabilization of Snail1 through NF-kB mediated CSN2 induction.
CSN2 induces Snail stabilization by inhibiting its ubiquitination

SNAI1|ubi@Nucleus

References
ce_re537( Cell Cycle DNA Repair ):
ubiqutinated PARP1 is degraded
PMID:21577210

SNAI1|unk@Nucleus

References
ce_re539( Cell Cycle DNA Repair ):
PARP1 poly(ADP)ribosylates SNAI1 and activates it and EMT program
PMID:21577210
ce_re537( Cell Cycle DNA Repair ):
ubiqutinated PARP1 is degraded

Modifications:
In compartment: Cytosol

SNAI1|pho|pho@Cytosol

In compartment: Nucleus

SNAI1@Nucleus
SNAI1|pho@Nucleus
SNAI1|ubi@Nucleus
SNAI1|unk@Nucleus

Participates in complexes:
In compartment: Nucleus

Participates in reactions:
As Reactant or Product:

As Catalyser: