e_re9( EMT ):
Wild-type p53 inhibits Slug protein expression.
Slug protein levels were significantly decreased in parallel with increased wtp53 accumulation.
Slug mRNA levels did not change indicating that Slug is not transcriptionally regulated by wtp53
e_re2( EMT ):
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
TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways
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.
Snail1 induces Snail2 transcription.
Snail is able to induce the expression of Slug and all other neural crest markers (Zic5, FoxD3, Twist and Ets1)
Snail2 activates the Snail2 promoter
Twist1 binds to an E-box on the proximate Snail2 promoter to induce its transcription.
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
Activation of KIT by binding to KITLG induces SNAI2 expression
e_re26( EMT ):
TCF3 (E47) is upregulated by Snail1, Snail2, Zeb1.
e_re523( EMT ):
Snail binds directly to the E-boxes of the promoters of claudin et occludin genes, resulting in complete repression of their promoter activity
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
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
e_re1216( EMT ):
Phosphorylations on p53 prevent its binding to MDM2.
S186 phosphorylation of MDM2 by AKT favors the binding of MDM2 to p53 and its following degradation.
Complex of p53, MDM2 and Slug faciliates the proteasomal degradation of Slug by MDM2.
In compartment: Nucleus
Participates in complexes:
In compartment: Nucleus
Participates in reactions:
As Reactant or Product:
- SNAI2@Nucleus + MDM2|S186_pho:p53*@Nucleus → MDM2|S186_pho:SNAI2:p53*@Nucleus
- MDM2|S186_pho:SNAI2:p53*@Nucleus → degraded
- SNAI2@Nucleus + CTBP1_2*@Nucleus + HDAC1@Nucleus + HDAC3@Nucleus → CTBP1_2*:HDAC1:HDAC3:SNAI2@Nucleus
- rSNAI2@Nucleus → SNAI2@Nucleus
- gBMI1@Nucleus → rBMI1@Nucleus
- gMDM2@Nucleus → rMDM2@Nucleus
- gHDAC1@Nucleus → rHDAC1@Nucleus
- gHDAC2@Nucleus → rHDAC2@Nucleus
- gSIN3A@Nucleus → rSIN3A@Nucleus
- gSNAI2@Nucleus → rSNAI2@Nucleus
- gTCF3@Nucleus → rTCF3@Nucleus
- gp21CIP1*@Nucleus → rp21CIP1*@Nucleus
- gE-Cadherin*@Nucleus → rE-Cadherin*@Nucleus
- gClaudin1*@Nucleus → rClaudin1*@Nucleus