Regulation of TP53 Expression and Degradation (Homo sapiens)

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12, 14, 19, 51, 54...16, 446610, 25, 45, 56, 69...13, 32, 59196017, 29, 30, 48, 64...9, 8818, 892, 31, 47, 7090199118223, 65, 11, 26, 621613, 32, 5934, 40, 56, 686056, 611837, 42811814, 29, 30, 643784, 9419, 21, 23, 25, 53...52, 758425, 84, 9455, 56cytosolplasma membranenucleoplasmK63polyUb CCNG1 GeneUBC(77-152) p-S166,S188-MDM2dimerPolyUb,p-S166,S188-MDM2 PolyUb,p-S166,S188-MDM2 homodimerPRDM1p-S166,S188,T218-MDM2 UBC(1-76) PPP2R1B K33polyUb p-S166,S188-MDM2MTOR TP53 TetramerCCNG1 Gene MDM4 UBC(229-304) PolyUb-TP53 ADPADPUBC(77-152) p14-ARF p-S166,S188-MDM2 PPP2CA DAXX PolyUb,p-S342,S367,S403-MDM4 TP53 UBC(153-228) UBC(153-228) PolyUb,p-S342,S367,S403-MDM4 UbMAPKAP1 UBB(77-152) PolyUb,p-S166,S188-MDM2 p-S166,S188-MDM2,MDM4p-S15,S20-TP53Tetramer:MDM2 GeneUBC(457-532) TP53 UBB(153-228) UBB(153-228) ATPUBC(609-684) UBB(153-228) UBB(1-76) ADPUBA52(1-76) p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53H2Op-S15,S20-TP53 PolyUb,p-S166,S188-MDM2:(PolyUb,p-S166,S188-MDM2, PolyUb,p-S342,S367,S403-MDM4)UBC(609-684) p-S166,S188-MDM2 p-S166,S188-MDM2dimer,p-S166,S188-MDM2:MDM4RFFL UBC(381-456) p-S166,S188-MDM2 CCNG1 PDPK1:PIP3ATPPPP2R5C MDM2p-S1981,Ac-K3016-ATMPolyUb-TP53 TetramerK29polyUb RNF34,RFFLp-S166,S188-MDM2 UBC(457-532) UBC(305-380) UBC(1-76) UBC(229-304) p-S346,S367,S403-MDM4 PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4p-T305,S472-AKT3 p-S346,S367,S403-MDM4 UBC(609-684) UBB(153-228) UBC(305-380) p-S166,S188-MDM2 UBC(533-608) UBC(381-456) p-T,p-S-AKTPPP2R1A p-S166,S188-MDM2 UBC(457-532) ATPPI(3,4,5)P3 RPS27A(1-76) PRDM1 K11polyUb K6polyUb PRR5 MDM2 GenePPP2R1B DNA Double StrandBreak ResponseUBC(153-228) H2Op-S166,S188-MDM2ADPDAXXp-S166,S188,T218-MDM2USP2 UBC(533-608) p-5S,T-MDM2UBA52(1-76) PPP2R5C ATPPolyUb,p-S15,S20-TP53 Tetramerp-T309,S474-AKT2 UBC(1-76) UBA52(1-76) p-S15,S20-TP53TetramerATPPolyUb,p-S15,S20-TP53 TP53 USP7TORC2 complexDAXX:(PolyUb,p-S166,S188-MDM2):USP7PRDM1:TP53 GenePP2A-PPP2R5CMDM2 Gene TP53 genePPP2A-PPPR5C:CCNG1:(p-T218-MDM2, p-S166-MDM2)CCNA2 TP53 gene PolyUb,p-S342,S367,S403-MDM4 p-S166,S188,T218-MDM2 RICTOR TP53USP2ATPp-S166,S188-MDM2 PDPK1 PolyUb,p-S342,S367,S403-MDM4 p-S166,S188-MDM2:MDM4p-S166,S188-MDM2:p-S346,S367,S403-MDM4RPS27A(1-76) TP53 p-T308,S473-AKT1 UBB(77-152) UbUBC(381-456) p-S166,S188-MDM2:(p-S166,S188-MDM2,p-S346,S367,S403-MDM4)PolyUb,p-S166,S188-MDM2 p-S166,S188-MDM2dimer,p-S166,S188-MDM2,MDM4:TP53PolyUbUBC(381-456) p-S166,S188-MDM2 PPP2CB UBC(1-76) p-S403-MDM4 UBB(1-76) H2OPRDM1 Gene Regulation of TP53Activity throughPhosphorylationp-S422-SGK1p-S166,S188-MDM2 UBA52(1-76) H2OUBC(229-304) p-S166,S188-MDM2 ADPCCNG1p-S15,S20-TP53 p14-ARF p-S15,S20-TP53 MLST8 UBC(77-152) UBB(77-152) USP7 p-S15,S20-TP53:PRDM1GenePHF20ADPp-T256,S422-SGK1UbUBC(533-608) p-S166,S188-MDM2 UbPolyUb-TP53 TetramerMDM2MDM4 CCNA1 USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4MDM4 PPP2R1A p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4ADPPiUBC(153-228) RNF34 ATPPIP3 activates AKTsignalingCCNA:p-CDK1/2MDM4 p-S166,S188-MDM2 K48polyUb K27polyUb p-S,3T-CHEK2UBC(77-152) UBC(457-532) UBB(77-152) p-T218,S166,S188-MDM2, p-S166,S188-MDM2SGK1MDM4 RPS27A(1-76) UBC(609-684) p-S166,S188-MDM2:p-S403-MDM4p14-ARFUBC(533-608) PolyUb,p-S166,S188-MDM2 UBC(305-380) TP53 Tetramer:CCNG1Genep-T161-CDK1 UBC(305-380) PPP2CA p-T160-CDK2 PRDM1 GeneUBB(1-76) PolyUb-TP53 UBC(229-304) UBB(1-76) MDM4 PolyUb,p-S166,S188-MDM2 PPP2CB RPS27A(1-76) 4, 7, 8, 15, 20...1840, 681915610, 45, 69, 7933, 4684846640, 56, 68


Description

TP53 (p53) tumor suppressor protein is a transcription factor that functions as a homotetramer (Jeffrey et al. 1995). The protein levels of TP53 are low in unstressed cells due to MDM2-mediated ubiquitination that triggers proteasome-mediated degradation of TP53 (Wu et al. 1993). The E3 ubiquitin ligase MDM2 functions as a homodimer/homo-oligomer or a heterodimer/hetero-oligomer with MDM4 (MDMX) (Linares et al. 2003, Toledo and Wahl 2007, Cheng et al. 2011, Wade et al. 2013).

Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).<p>While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005). View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 6806003
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101453view11:32, 1 November 2018ReactomeTeamreactome version 66
100991view21:11, 31 October 2018ReactomeTeamreactome version 65
100527view19:44, 31 October 2018ReactomeTeamreactome version 64
100074view16:28, 31 October 2018ReactomeTeamreactome version 63
99625view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99232view12:44, 31 October 2018ReactomeTeamreactome version 62
93820view13:38, 16 August 2017ReactomeTeamreactome version 61
93366view11:21, 9 August 2017ReactomeTeamreactome version 61
87115view18:24, 18 July 2016EgonwOntology Term : 'regulatory pathway' added !
86451view09:18, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA:p-CDK1/2ComplexR-HSA-4088020 (Reactome)
CCNG1 Gene ProteinENSG00000113328 (Ensembl)
CCNG1 GeneGeneProductENSG00000113328 (Ensembl)
CCNG1 ProteinP51959 (Uniprot-TrEMBL)
CCNG1ProteinP51959 (Uniprot-TrEMBL)
DAXX ProteinQ9UER7 (Uniprot-TrEMBL)
DAXX:(PolyUb,p-S166,S188-MDM2):USP7ComplexR-HSA-3222079 (Reactome)
DAXXProteinQ9UER7 (Uniprot-TrEMBL)
DNA Double Strand Break ResponsePathwayR-HSA-5693606 (Reactome) DNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. For a recent review, please refer to Ciccia and Elledge, 2010.
H2OMetaboliteCHEBI:15377 (ChEBI)
K11polyUb R-HSA-6782596 (Reactome)
K27polyUb R-HSA-6782588 (Reactome)
K29polyUb R-HSA-6782589 (Reactome)
K33polyUb R-HSA-6782629 (Reactome)
K48polyUb R-HSA-6782465 (Reactome)
K63polyUb R-HSA-6782513 (Reactome)
K6polyUb R-HSA-6782613 (Reactome)
MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MDM2 Gene ProteinENSG00000135679 (Ensembl)
MDM2 GeneGeneProductENSG00000135679 (Ensembl)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MDM4 ProteinO15151 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP3ComplexR-HSA-109697 (Reactome)
PHF20ProteinQ9BVI0 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PP2A-PPP2R5CComplexR-HSA-6792873 (Reactome)
PPP2A-PPPR5C:CCNG1:(p-T218-MDM2, p-S166-MDM2)ComplexR-HSA-6792868 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PRDM1 Gene ProteinENSG00000057657 (Ensembl)
PRDM1 GeneGeneProductENSG00000057657 (Ensembl)
PRDM1 ProteinO75626 (Uniprot-TrEMBL)
PRDM1:TP53 GeneComplexR-HSA-6804203 (Reactome)
PRDM1ProteinO75626 (Uniprot-TrEMBL)
PRR5 ProteinP85299 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
PolyUb,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
PolyUb,p-S15,S20-TP53 TetramerComplexR-HSA-6804448 (Reactome)
PolyUb,p-S166,S188-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
PolyUb,p-S166,S188-MDM2 homodimerComplexR-HSA-6804935 (Reactome)
PolyUb,p-S166,S188-MDM2:(PolyUb,p-S166,S188-MDM2, PolyUb,p-S342,S367,S403-MDM4)ComplexR-HSA-6805029 (Reactome)
PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4ComplexR-HSA-6804937 (Reactome)
PolyUb,p-S342,S367,S403-MDM4 ProteinO15151 (Uniprot-TrEMBL)
PolyUb-TP53 ProteinP04637 (Uniprot-TrEMBL)
PolyUb-TP53 TetramerComplexR-HSA-3209186 (Reactome)
PolyUb-TP53 TetramerComplexR-HSA-8856287 (Reactome)
PolyUbComplexR-HSA-6782682 (Reactome)
RFFL ProteinQ8WZ73 (Uniprot-TrEMBL)
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
RNF34 ProteinQ969K3 (Uniprot-TrEMBL)
RNF34,RFFLComplexR-HSA-6804437 (Reactome)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Regulation of TP53

Activity through

Phosphorylation
PathwayR-HSA-6804756 (Reactome) Phosphorylation of TP53 (p53) at the N-terminal serine residues S15 and S20 plays a critical role in protein stabilization as phosphorylation at these sites interferes with binding of the ubiquitin ligase MDM2 to TP53. Several different kinases can phosphorylate TP53 at S15 and S20. In response to double strand DNA breaks, S15 is phosphorylated by ATM (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998), and S20 by CHEK2 (Chehab et al. 1999, Chehab et al. 2000, Hirao et al. 2000). DNA damage or other types of genotoxic stress, such as stalled replication forks, can trigger ATR-mediated phosphorylation of TP53 at S15 (Lakin et al. 1999, Tibbetts et al. 1999) and CHEK1-mediated phosphorylation of TP53 at S20 (Shieh et al. 2000). In response to various types of cell stress, NUAK1 (Hou et al. 2011), CDK5 (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008), AMPK (Jones et al. 2005) and TP53RK (Abe et al. 2001, Facchin et al. 2003) can phosphorylate TP53 at S15, while PLK3 (Xie, Wang et al. 2001, Xie, Wu et al. 2001) can phosphorylate TP53 at S20.

Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).

MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).

NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).

The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).

Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012).

SGK1ProteinO00141 (Uniprot-TrEMBL)
TORC2 complexComplexR-HSA-198626 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Tetramer:CCNG1 GeneComplexR-HSA-6791405 (Reactome)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TP53 gene ProteinENSG00000141510 (Ensembl)
TP53 geneGeneProductENSG00000141510 (Ensembl)
TP53ProteinP04637 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
USP2 ProteinO75604 (Uniprot-TrEMBL)
USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4ComplexR-HSA-6782767 (Reactome)
USP2ProteinO75604 (Uniprot-TrEMBL)
USP7 ProteinQ93009 (Uniprot-TrEMBL)
USP7ProteinQ93009 (Uniprot-TrEMBL)
UbComplexR-HSA-68524 (Reactome)
p-5S,T-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S,3T-CHEK2ProteinO96017 (Uniprot-TrEMBL)
p-S15,S20-TP53 Tetramer:MDM2 GeneComplexR-HSA-3700998 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15,S20-TP53:PRDM1 GeneComplexR-HSA-6804190 (Reactome)
p-S166,S188,T218-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
p-S166,S188,T218-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
ComplexR-HSA-6804885 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ComplexR-HSA-6804745 (Reactome)
p-S166,S188-MDM2 dimerComplexR-HSA-6804933 (Reactome)
p-S166,S188-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
p-S166,S188-MDM2,MDM4ComplexR-HSA-6804750 (Reactome)
p-S166,S188-MDM2:(p-S166,S188-MDM2,p-S346,S367,S403-MDM4)ComplexR-HSA-6805030 (Reactome)
p-S166,S188-MDM2:MDM4ComplexR-HSA-6804932 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4ComplexR-HSA-6804936 (Reactome)
p-S166,S188-MDM2:p-S403-MDM4ComplexR-HSA-6804939 (Reactome)
p-S166,S188-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
p-S346,S367,S403-MDM4 ProteinO15151 (Uniprot-TrEMBL)
p-S403-MDM4 ProteinO15151 (Uniprot-TrEMBL)
p-S422-SGK1ProteinO00141 (Uniprot-TrEMBL)
p-T,p-S-AKTComplexR-HSA-202074 (Reactome)
p-T160-CDK2 ProteinP24941 (Uniprot-TrEMBL)
p-T161-CDK1 ProteinP06493 (Uniprot-TrEMBL)
p-T218,S166,S188-MDM2, p-S166,S188-MDM2ComplexR-HSA-6792895 (Reactome)
p-T256,S422-SGK1ProteinO00141 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p14-ARF ProteinQ8N726 (Uniprot-TrEMBL)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53ComplexR-HSA-6804999 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4ComplexR-HSA-6804995 (Reactome)
p14-ARFProteinQ8N726 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-198599 (Reactome)
ADPArrowR-HSA-349426 (Reactome)
ADPArrowR-HSA-349455 (Reactome)
ADPArrowR-HSA-6793661 (Reactome)
ADPArrowR-HSA-6795290 (Reactome)
ADPArrowR-HSA-6795460 (Reactome)
ADPArrowR-HSA-6795473 (Reactome)
ADPArrowR-HSA-6804955 (Reactome)
ATPR-HSA-198599 (Reactome)
ATPR-HSA-349426 (Reactome)
ATPR-HSA-349455 (Reactome)
ATPR-HSA-6793661 (Reactome)
ATPR-HSA-6795290 (Reactome)
ATPR-HSA-6795460 (Reactome)
ATPR-HSA-6795473 (Reactome)
ATPR-HSA-6804955 (Reactome)
CCNA:p-CDK1/2mim-catalysisR-HSA-6793661 (Reactome)
CCNG1 GeneR-HSA-6791409 (Reactome)
CCNG1 GeneR-HSA-6792491 (Reactome)
CCNG1ArrowR-HSA-6792491 (Reactome)
CCNG1ArrowR-HSA-6792863 (Reactome)
CCNG1R-HSA-6792871 (Reactome)
DAXX:(PolyUb,p-S166,S188-MDM2):USP7ArrowR-HSA-3222072 (Reactome)
DAXX:(PolyUb,p-S166,S188-MDM2):USP7R-HSA-3215295 (Reactome)
DAXX:(PolyUb,p-S166,S188-MDM2):USP7mim-catalysisR-HSA-3215295 (Reactome)
DAXXArrowR-HSA-3215295 (Reactome)
DAXXR-HSA-3222072 (Reactome)
H2OR-HSA-3215295 (Reactome)
H2OR-HSA-3215310 (Reactome)
H2OR-HSA-5689972 (Reactome)
H2OR-HSA-6792863 (Reactome)
MDM2 GeneR-HSA-3700992 (Reactome)
MDM2 GeneR-HSA-3700997 (Reactome)
MDM2ArrowR-HSA-3700992 (Reactome)
MDM2ArrowR-HSA-6792863 (Reactome)
MDM2ArrowR-HSA-6795667 (Reactome)
MDM2R-HSA-198599 (Reactome)
MDM2R-HSA-6795460 (Reactome)
MDM2R-HSA-6795667 (Reactome)
PDPK1:PIP3mim-catalysisR-HSA-6795473 (Reactome)
PHF20TBarR-HSA-5633460 (Reactome)
PP2A-PPP2R5CArrowR-HSA-6792863 (Reactome)
PP2A-PPP2R5CR-HSA-6792871 (Reactome)
PPP2A-PPPR5C:CCNG1:(p-T218-MDM2, p-S166-MDM2)ArrowR-HSA-6792871 (Reactome)
PPP2A-PPPR5C:CCNG1:(p-T218-MDM2, p-S166-MDM2)R-HSA-6792863 (Reactome)
PPP2A-PPPR5C:CCNG1:(p-T218-MDM2, p-S166-MDM2)mim-catalysisR-HSA-6792863 (Reactome)
PRDM1 GeneR-HSA-6804191 (Reactome)
PRDM1 GeneR-HSA-6804193 (Reactome)
PRDM1:TP53 GeneArrowR-HSA-6804194 (Reactome)
PRDM1:TP53 GeneTBarR-HSA-6804188 (Reactome)
PRDM1ArrowR-HSA-6804193 (Reactome)
PRDM1R-HSA-6804194 (Reactome)
PiArrowR-HSA-6792863 (Reactome)
PolyUb,p-S15,S20-TP53 TetramerArrowR-HSA-6804441 (Reactome)
PolyUb,p-S166,S188-MDM2 homodimerArrowR-HSA-6804942 (Reactome)
PolyUb,p-S166,S188-MDM2:(PolyUb,p-S166,S188-MDM2, PolyUb,p-S342,S367,S403-MDM4)R-HSA-3222072 (Reactome)
PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4ArrowR-HSA-6804724 (Reactome)
PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4R-HSA-6805022 (Reactome)
PolyUb-TP53 TetramerArrowR-HSA-6793685 (Reactome)
PolyUb-TP53 TetramerArrowR-HSA-6804879 (Reactome)
PolyUb-TP53 TetramerR-HSA-3215310 (Reactome)
PolyUb-TP53 TetramerR-HSA-6793685 (Reactome)
PolyUbArrowR-HSA-5689972 (Reactome)
R-HSA-198599 (Reactome) AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Mayo and Donner 2001, Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of the E3 ubiquitin-protein ligase MDM2 promotes nuclear localization and interferes with the interaction between MDM2 and p14-ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001, Mayo and Donner 2001).
R-HSA-3215295 (Reactome) In the presence of DAXX, USP7 deubiquitinates MDM2. DAXX expression therefore prolongs MDM2 half-life and inhibits TP53 activation (Tang et al. 2006). In the absence of DAXX or when DNA damage response is activated (Tang et al. 2006), USP7 associates with ubiquitinated TP53 rather than ubiquitinated MDM2 (Li et al. 2004, Sheng et al. 2006, Hu et al. 2006). USP7 also deubiquitinates MDM4 (MDMX) (Meulmeester et al. 2005, Sarkari et al. 2010). The role of DAXX in deubiquitination of MDM4 has not been examined.
R-HSA-3215310 (Reactome) USP7 (HAUSP) can deubiquitinate TP53, thereby prolonging TP53 half-life and enhancing TP53 activity (Li et al. 2002, Li et al. 2004, Sheng et al. 2006, Hu et al. 2006).
R-HSA-3222072 (Reactome) DAXX paired amphipathic helix domain 2 (PAH2) binds MDM2, while DAXX PAH1 domain and acid rich region simultaneously bind USP7 (HAUSP) (Tang et al. 2006), forming a tripartite complex.
R-HSA-349426 (Reactome) CHEK2 (Chk2) kinase is required for phosphorylation of MDM4 at serine residues S342 and S367 in vivo. CHEK2-mediated phosphorylation stimulates MDM4 ubiquitination by MDM2 and subsequent degradation (Chen et al. 2005).
R-HSA-349455 (Reactome) Human MDM4 (MDMX) is phosphorylated on serine residue S403 by ATM. This site is important for MDM2-mediated ubiquitination of MDM4 after induction of double strand DNA breaks (Pereg et al. 2005, Chen et al. 2005).
R-HSA-3700992 (Reactome) Binding of TP53 (p53) to the p53 response element in the first intron of the MDM2 gene stimulates MDM2 transcription (Wu et al. 1993).
R-HSA-3700997 (Reactome) TP53 (p53) binds the p53 response element in the first intron of the MDM2 gene (Wu et al. 1993).
R-HSA-5633460 (Reactome) The N-terminal portion of MDM2 binds the N-terminal transactivation domain of TP53 (p53) and inhibits transcriptional transactivation by TP53 (Momand et al. 1992, Oliner et al. 1992, Oliner et al. 1993, Chen et al. 1993).
R-HSA-5689972 (Reactome) The ubiquitin protease USP2 deubiquitinates MDM2 and MDM4 but not TP53 (Stevenson et al. 2007, Allende-Vega et al. 2010).
R-HSA-6791409 (Reactome) TP53 (p53) binds the p53 response element in the first intron of cyclin G1 (CCNG1) gene. An additional p53 response element may be located in the CCNG1 promoter (Okamoto and Beach 1994, Zauberman et al. 1995, Endo et al. 1996).
R-HSA-6792491 (Reactome) Upon binding to the p53 response elements in the promoter and/or the first intron of CCNG1 (cyclin G1) gene, TP53 induces CCNG1 transcription (Okamoto and Beach 1994, Zauberman et al. 1995, Endo et al. 1996).
R-HSA-6792863 (Reactome) The protein serine/threonine phosphatase complex PP2A, recruited to MDM2 through interaction of the PP2A regulatory subunit PPP2R5C and cyclin G1 (CCNG1) dephosphorylates MDM2 on threonine residue T218 (T218 in human MDM2 corresponds to T216 in mouse Mdm2). Dephosphorylation of T218 increases the affinity of MDM2 for TP53 (p53), leading to p53 down-regulation (Okamoto et al. 2002).

CCNG1-recruited PP2A can also dephosphorylate serine residue S166 of human MDM2 (Okamoto et al. 2002).

R-HSA-6792871 (Reactome) CCNG1 (cyclin G1) simultaneously interacts with the regulatory subunit of the PP2A protein phosphatase complex, PPP2R5C (Okamoto et al. 1996), and MDM2, thus recruiting the PP2A complex to MDM2 (Okamoto et al. 2002).
R-HSA-6793661 (Reactome) CDK1 or CDK2 in complex with CCNA (cyclin A) phosphorylates MDM2 at threonine residue T218. Phosphorylation of MDM2 at T218 increases its affinity for p14-ARF and reduces its affinity for TP53 (p53), thus resulting in TP53 upregulation (Zhang and Prives 2001).
R-HSA-6793666 (Reactome) AKT- or SGK1-phosphorylated MDM2 residues S166 and S188 are in the vicinity of the MDM2 nuclear localization signal. MDM2 phosphorylation by AKT or SGK1 leads to MDM2 translocation from the cytosol to the nucleus (Mayo and Donner 2001).
R-HSA-6793685 (Reactome) Upon MDM2-mediated ubiquitination, TP53 is exported from the nucleus to the cytosol. TP53 nuclear export requires the nuclear export sequence (NES) of TP53, but not the NES of MDM2 (Boyd et al. 2000. Geyer et al. 2000).
R-HSA-6795290 (Reactome) The TORC2 complex phosphorylates SGK1 at serine residue S422, located in the carboxy-terminal hydrophobic motif of SGK1. Phosphorylation at S422 contributes to SGK1 activation (Garcia-Martinez and Alessi 2008, Lu et al. 2010).
R-HSA-6795460 (Reactome) SGK1 phosphorylates MDM2 at serine residues S166 and S188, resulting in MDM2 activation (Amato et al. 2009, Lyo et al. 2010). SGK1 may play a more prominent role in MDM2 activation than AKT (Lyo et al. 2010).
R-HSA-6795473 (Reactome) PDPK1 (PDK1) activates SGK1 by phosphorylating threonine residue T256, located in the activation loop of SGK1. Phosphorylation of SGK1 at S422 facilitates subsequent phosphorylation at T256 (Kobayashi and Cohen 1999).
R-HSA-6795667 (Reactome) Unphosphorylated MDM2 is exported from the nucleus into the cytosol (Mayo and Donner 2001).
R-HSA-6804188 (Reactome) Binding of PRDM1 (BLIMP1) to the promoter region of the TP53 (p53) gene inhibits TP53 transcription (Yan et al. 2007) probably by inducing repressive methylation of the TP53 promoter (Weige et al. 2014).
R-HSA-6804191 (Reactome) TP53 (p53) binds the p53 response element in the third intron of the PRDM1 (BLIMP1) gene (Yan et al. 2007).
R-HSA-6804193 (Reactome) Binding of TP53 (p53) to the p53 response element in the third intron of the PRDM1 (BLIMP1) gene stimulates BLIMP1 transcription (Yan et al. 2007).
R-HSA-6804194 (Reactome) PRDM1 (BLIMP1) zinc finger transcription factor binds in vicinity of the transcription start site of the TP53 (p53) gene (Yan et al. 2007).
R-HSA-6804441 (Reactome) E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate TP53 (p53) phosphorylated at the N-terminus and target it for proteasome-mediated degradation (Yang et al. 2007).
R-HSA-6804724 (Reactome) Once MDM4 is phosphorylated by ATM and CHEK2 in response to DNA damage, MDM2 ubiquitinates MDM4 and targets it for degradation (Chen et al. 2005, Pereg et al. 2005). The presence of MDM4 stimulates auto-ubiquitination of MDM2 (Linares et al. 2003).
R-HSA-6804741 (Reactome) To efficiently function as an E3 ubiquitin ligase, MDM2 has to form dimers or higher order oligomers. MDM2 can homodimerize (Cheng et al. 2011) or heterodimerize with MDM4 (MDMX) (Sharp et al. 1999, Huang et al. 2011, Pant et al. 2011). Dimerization involves the RING domain of MDM2 and/or MDM4. Heterodimers of MDM2 and MDM4 may be particularly important during embryonic development (Pant et al. 2011).
R-HSA-6804762 (Reactome) TP53 (p53) functions as a stable homotetramer. The tetramerization domain is located within the C-terminus (Stenger et al. 1994, Waterman et al. 1995, Jeffrey et al. 1995, Wang et al. 1995).
R-HSA-6804879 (Reactome) MDM2 is an ubiquitin ligase whose expression is positively regulated by TP53 (p53) (Wu et al. 1993). MDM2 binds TP53 tetramer (Maki 1999) and promotes its ubiquitination and subsequent degradation (Fuchs et al. 1998). Formation of MDM2 homodimers (Cheng et al. 2011) or heterodimers with MDM4 (MDMX) is needed for efficient ubiquitination of TP53 (Linares et al. 2003). While MDM2-TP53 binding occurs at the amino-terminus of TP53, MDM2 ubiquitinates TP53 lysine residues at the carboxy-terminus. Acetylation of those lysines can inhibit MDM2-dependent ubiquitination (Li et al. 2002).
R-HSA-6804942 (Reactome) MDM2 undergoes auto-ubiquitination (Fang et al. 2000). Formation of homodimers may not be necessary for auto-ubiquitination (Cheng et al. 2011).
R-HSA-6804955 (Reactome) ATM phosphorylates MDM2 on three serine residues (S386, S395, S407) and one threonine residue (T419) in vicinity to the RING domain. ATM-mediated phosphorylation of MDM2 in response to DNA damage (DNA double strand breaks) prevents MDM2 dimerization, binding of TP53 (p53) and MDM2-mediated ubiquitination of TP53 (Cheng et al. 2009, Cheng et al. 2011).
R-HSA-6804996 (Reactome) Binding of p14-ARF to MDM2 decreases the half-life of MDM2, likely through promoting MDM2 degradation. Thus, p14-ARF inhibits MDM2-mediated ubiquitination and degradation of TP53 (Zhang et al. 1998).
R-HSA-6804998 (Reactome) p14-ARF forms a complex with TP53-bound MDM2 by interacting with the C-terminus of MDM2, while the N-terminus of MDM2 is involved in TP53 (p53) binding. p14-ARF cannot associate with TP53 in the absence of MDM2 (Zhang et al. 1998).
R-HSA-6805022 (Reactome) The ubiquitin protease USP2 forms a tripartite complex with MDM2 and MDM4 (MDMX) by binding to the ubiquitinated heterodimer of MDM2 and MDM4 (Allende-Vega et al. 2010).
RNF34,RFFLmim-catalysisR-HSA-6804441 (Reactome)
SGK1R-HSA-6795290 (Reactome)
TORC2 complexmim-catalysisR-HSA-6795290 (Reactome)
TP53 Tetramer:CCNG1 GeneArrowR-HSA-6791409 (Reactome)
TP53 Tetramer:CCNG1 GeneArrowR-HSA-6792491 (Reactome)
TP53 TetramerArrowR-HSA-3215310 (Reactome)
TP53 TetramerArrowR-HSA-6804762 (Reactome)
TP53 TetramerArrowR-HSA-6804996 (Reactome)
TP53 TetramerR-HSA-5633460 (Reactome)
TP53 TetramerR-HSA-6791409 (Reactome)
TP53 geneR-HSA-6804188 (Reactome)
TP53 geneR-HSA-6804194 (Reactome)
TP53ArrowR-HSA-6804188 (Reactome)
TP53R-HSA-6804762 (Reactome)
USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4ArrowR-HSA-6805022 (Reactome)
USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4R-HSA-5689972 (Reactome)
USP2:PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4mim-catalysisR-HSA-5689972 (Reactome)
USP2ArrowR-HSA-5689972 (Reactome)
USP2R-HSA-6805022 (Reactome)
USP7ArrowR-HSA-3215295 (Reactome)
USP7R-HSA-3222072 (Reactome)
USP7mim-catalysisR-HSA-3215310 (Reactome)
UbArrowR-HSA-3215295 (Reactome)
UbArrowR-HSA-3215310 (Reactome)
UbR-HSA-6804441 (Reactome)
UbR-HSA-6804724 (Reactome)
UbR-HSA-6804879 (Reactome)
UbR-HSA-6804942 (Reactome)
p-5S,T-MDM2ArrowR-HSA-6804955 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-349426 (Reactome)
p-S15,S20-TP53 Tetramer:MDM2 GeneArrowR-HSA-3700992 (Reactome)
p-S15,S20-TP53 Tetramer:MDM2 GeneArrowR-HSA-3700997 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-3700997 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804191 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804441 (Reactome)
p-S15,S20-TP53:PRDM1 GeneArrowR-HSA-6804191 (Reactome)
p-S15,S20-TP53:PRDM1 GeneArrowR-HSA-6804193 (Reactome)
p-S166,S188,T218-MDM2ArrowR-HSA-6793661 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
ArrowR-HSA-5633460 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
R-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
R-HSA-6804998 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
mim-catalysisR-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ArrowR-HSA-6804741 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ArrowR-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
R-HSA-5633460 (Reactome)
p-S166,S188-MDM2 dimerR-HSA-6804942 (Reactome)
p-S166,S188-MDM2 dimermim-catalysisR-HSA-6804942 (Reactome)
p-S166,S188-MDM2,MDM4R-HSA-6804741 (Reactome)
p-S166,S188-MDM2:(p-S166,S188-MDM2,p-S346,S367,S403-MDM4)ArrowR-HSA-3215295 (Reactome)
p-S166,S188-MDM2:MDM4R-HSA-349455 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4ArrowR-HSA-349426 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4ArrowR-HSA-5689972 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4R-HSA-6804724 (Reactome)
p-S166,S188-MDM2:p-S346,S367,S403-MDM4mim-catalysisR-HSA-6804724 (Reactome)
p-S166,S188-MDM2:p-S403-MDM4ArrowR-HSA-349455 (Reactome)
p-S166,S188-MDM2:p-S403-MDM4R-HSA-349426 (Reactome)
p-S166,S188-MDM2ArrowR-HSA-198599 (Reactome)
p-S166,S188-MDM2ArrowR-HSA-6793666 (Reactome)
p-S166,S188-MDM2ArrowR-HSA-6795460 (Reactome)
p-S166,S188-MDM2R-HSA-6793661 (Reactome)
p-S166,S188-MDM2R-HSA-6793666 (Reactome)
p-S166,S188-MDM2R-HSA-6804741 (Reactome)
p-S166,S188-MDM2R-HSA-6804955 (Reactome)
p-S1981,Ac-K3016-ATMTBarR-HSA-6804741 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-349455 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-6804955 (Reactome)
p-S422-SGK1ArrowR-HSA-6795290 (Reactome)
p-S422-SGK1R-HSA-6795473 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-198599 (Reactome)
p-T218,S166,S188-MDM2, p-S166,S188-MDM2R-HSA-6792871 (Reactome)
p-T256,S422-SGK1ArrowR-HSA-6795473 (Reactome)
p-T256,S422-SGK1mim-catalysisR-HSA-6795460 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53ArrowR-HSA-6804998 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53R-HSA-6804996 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4ArrowR-HSA-6804996 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4TBarR-HSA-6804879 (Reactome)
p14-ARFR-HSA-6804998 (Reactome)

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