Identifiers
cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4)
HUGO:CDKN2B, HGNC:1788, ENTREZ:1030, GENECARDS:GC09M021992
HUGO:CDKN2B HGNC:1788 ENTREZ:1030 UNIPROT:P42772 GENECARDS:CDKN2B REACTOME:87041 KEGG:1030 ATLASONC:CDKN2BID187ch9p21 WIKI:CDKN2B
Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
EMT Senescence / SENESCENCE
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / PI3K_AKT_MTOR
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:10331086
CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family
INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d
INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks
INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3)
The vast majority of INK4 proteins are not found in complexes containing cyclins D.
PMID:8078588
p15INK4B is a potential effector of TGFB-induced cell cycle arrest
PMID:22943793
TGFB induces expression of p15INK4B and represses expression of c-Myc
p15INK4B is able to prevent cyclin D-CDK4/6 complex formation
p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes.
These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle.
PMID:12542976
PMID:20673124
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:10331086
CDK inhibitors are classified into 2 families: Cip/Kip family and INK4 family
INK4 family consists of p16INK4a, p15INK4B, p18INK4c, p19INK4d
INK4 family spcially interacts with Cdk4 and Cdk6 but not other Cdks
INK4 binding prevents the association of Cdk4 and Cdk6 with the D-type cyclins (D1, D2, D3)
The vast majority of INK4 proteins are not found in complexes containing cyclins D.
PMID:8078588
p15INK4B is a potential effector of TGFB-induced cell cycle arrest
PMID:22943793
TGFB induces expression of p15INK4B and represses expression of c-Myc
p15INK4B is able to prevent cyclin D-CDK4/6 complex formation
p15INK4B displaces p21CIP and p27KIP1 from cyclin D-CDK4/6 complexes.
These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and therby inhibit cell cycle.
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)
PMID:11283614
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
→ rp15INK4B*@Nucleus
→ p15INK4B*@Cytosol
→ rp15INK4B*@Nucleus