Identifiers
NAME:MIZ1*:SMAD2:SMAD3:SMAD4:SP1
Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
References
PMID:11013220
Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene
This interaction provides a mechanism underlying the TGFB-induced growth arrest
PMID:11283614
Miz1: a Myc-interacting Zinc-finger protein that recognizes certain transcriptional initiator elements
One of this transcriptional initiator element contains the sequence 5'-CCCACTCTGC corresponding to the p15INK4B transcriptional intiator
Physical interaction between Smad proteins and Miz-1:
-Immunoprecipitation of endogenous Smad2 and Smad3 followed by anti-Miz western bloting provided evidence for an association
-This association was stimulated by addition of TGFB
-Interaction was observed between Miz1 and Smad3 and Smad4 but no clear interaction was observed between Miz1 and Smad2
-Smad3 and weakly Smad4 can directly and selectively bind to Miz1 through the MH1 domain
-Although Sp1-Smad interactions have been reported, Sp1 does not directly bind to Miz1, even in the presence of TGFB.
-The Smad-interaction region of Miz1 does not overlap with the Myc-interaction region.
-Myc did not inhibit the Smad-Miz1 interaction
-Miz1 can bridge Smad proteins and Myc when these proteins coexist.
em_emtc_emtc_re250( EMT Senescence ):
PMID:11283613
Miz-1 regulates expression of p15INK4b
The Myc/Miz1 complex binds to the p15 promoter
Myc inhibits binding of p300 to Miz-1
Myc inhibits expression of p15INK4B by binding to Miz-1 (Myc represses p15INK4B by interacting with Miz1)
Disruption of the Myc-Miz1 interaction prevents repression of p15INK4B by Myc.
TGFB relieves Myc-mediated repression of p15INK4B by downregulating Myc bound to the p15INK4B transcriptional initiator region.
At the same time TGFB induces the formation of a Smad transcriptional complex that recognizes the p15INK4B promoter.
Is is proposed that by relieving the Myc-mediated repression of p15INK4B, TGFB allows this gene to be activated by the Smad complex.
TGFB signaling controls p15INK4B activation by 2 coupled events: transactivation and relief of repression.
PMID:10454538
Myc prevents inhibition of G1 CDKs by TGFB.
Inhibition of the p15 promoter by c-Myc.
Enforced expression of Myc abrogates p15INK4B induction and CDK inhibition by TGFB
Myc downregulation by TGFB is required for Activation of the p15Ink4b G1 Arrest Pathway
3 populations of endogenous CDK4: Latent pools (400 kDa, source of CDK4 for Cyclin D), Active CDK4-CyclinD complex, Inactive monomeric CDK4
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.
PMID:17550342
SNAI2 induces p21CIP1 (CDKN1A) expression
PMID:23869868
PMID:23140366
p53 transactivate p21
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