Regulation of TP53 activity through association with cofactors (Homo sapiens)

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7, 10, 19, 23, 25...60, 104, 121, 14050, 6840, 52, 80, 10477, 315, 2829, 44, 61, 108915, 287, 3151, 67, 73cytosolnucleoplasmp-S15,S20-TP53 PPP1R13L TP73 PHF20 PPP1R13B p-S15,S20-TP53Tetramer:ZNF385Ap-S15,S20-TP53 Me2-K370,K382-TP53Tetramerp-S15,S20-TP53Tetramer:POU4F2p-T305,S472-AKT3 p-S291-PHF20Me2K-370,382-TP53 PHF20POU4F1TP53 TP53:BANPp-S15,S20-TP53 PPP1R13B TP53 TetramerTP63 p-S15,S20-TP53 p-S15,S20-TP53 p-T308,S473-AKT1 POU4F2ZNF385A PHF20:Me2-K370,K382-TP53 TetramerADPp-S291-PHF20TP73 (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ZNF385A Gene Regulation of TP53Activity throughPhosphorylation(p-S15,S20-TP53,TP63,TP73):PPP1R13LTP53 Me2K-370,382-TP53 TP73 ATPPPP1R13Lp-S15,S20-TP53,TP63,TP73p-S15,S20-TP53 TP53BP2 PPP1R13B,TP53BP2ZNF385ATP53 RegulatesTranscription ofCell Death Genesp-S15,S20-TP53 p-S15,S20-TP53Tetramer:ZNF385AGeneBANPBANP p-S15,S20-TP53Tetramer:POU4F1POU4F1 TP63 TP63 p-T309,S474-AKT2 p-S15,S20-TP53 p-S15,S20-TP53TetramerActive AKTZNF385A GeneTP53BP2 POU4F2 TP53 RegulatesTranscription ofCell Cycle Genes68104, 1219129, 443, 4, 9, 11, 14...1, 2, 7, 8, 12...76, 21, 27, 36, 38...3151, 73


Description

Association of TP53 (p53) with various transcriptional co-factors can promote, inhibit or provide specificity towards either transcription of cell cycle arrest genes or transcription of cell death genes. Binding of the zinc finger protein ZNF385A (HZF), which is a transcriptional target of TP53, stimulates transcription of cell cycle arrest genes, such as CDKN1A (Das et al. 2007). Binding of POU4F1 (BRN3A) to TP53 also stimulates transcription of cell cycle arrest genes while inhibiting transcription of pro-apoptotic genes (Budhram-Mahadeo et al. 1999, Hudson et al. 2005).

Binding of ASPP family proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) to TP53 stimulates transcription of pro-apoptotic TP53 targets (Samuels-Lev et al. 2001, Bergamaschi et al. 2004). Binding of the ASPP family member PPP1R13L (iASSP) inhibits TP53-mediated activation of pro-apoptotic genes probably by interfering with binding of stimulatory ASPPs to TP53 (Bergamaschi et al. 2003). Transcription of pro-apoptotic genes is also stimulated by binding of TP53 to POU4F2 (BRN3B) (Budrham-Mahadeo et al. 2006, Budhram-Mahadeo et al. 2014) or to hCAS/CSE1L (Tanaka et al. 2007).<p>Binding of co-factors to TP53 can also affect protein stability. For example, PHF20 binds to TP53 dimethylated on lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s) and interferes with MDM2 binding, resulting in prolonged TP53 half-life (Cui et al. 2012). Long noncoding RNAs can contribute to p53-dependent transcriptional responses (Huarte et al. 2010). For a general review on this topic, see Espinosa 2008, Beckerman and Prives 2010, Murray-Zmijewski et al. 2008, An et al. 2004 and Barsotti and Prives 2010. View original pathway at:Reactome.</div>

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  117. Ezzeddine N, Chen CY, Shyu AB.; ''Evidence providing new insights into TOB-promoted deadenylation and supporting a link between TOB's deadenylation-enhancing and antiproliferative activities.''; PubMed Europe PMC Scholia
  118. Jain N, Gupta S, Sudhakar Ch, Radha V, Swarup G.; ''Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin.''; PubMed Europe PMC Scholia
  119. Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B.; ''14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage.''; PubMed Europe PMC Scholia
  120. Hudson CD, Morris PJ, Latchman DS, Budhram-Mahadeo VS.; ''Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate.''; PubMed Europe PMC Scholia
  121. Li HH, Li AG, Sheppard HM, Liu X.; ''Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression.''; PubMed Europe PMC Scholia
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History

View all...
CompareRevisionActionTimeUserComment
116687view14:18, 9 May 2021EweitzModified title
114818view16:31, 25 January 2021ReactomeTeamReactome version 75
113263view11:33, 2 November 2020ReactomeTeamReactome version 74
112478view15:43, 9 October 2020ReactomeTeamReactome version 73
101389view11:27, 1 November 2018ReactomeTeamreactome version 66
100927view21:03, 31 October 2018ReactomeTeamreactome version 65
100466view19:37, 31 October 2018ReactomeTeamreactome version 64
100012view16:21, 31 October 2018ReactomeTeamreactome version 63
99565view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99189view12:42, 31 October 2018ReactomeTeamreactome version 62
93781view13:36, 16 August 2017ReactomeTeamreactome version 61
93313view11:20, 9 August 2017ReactomeTeamreactome version 61
87634view08:54, 25 July 2016LindarieswijkOntology Term : 'p53 signaling pathway' added !
86399view09:17, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ComplexR-HSA-6799788 (Reactome)
(p-S15,S20-TP53,TP63,TP73):PPP1R13LComplexR-HSA-6799745 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTComplexR-HSA-202072 (Reactome)
BANP ProteinQ8N9N5 (Uniprot-TrEMBL)
BANPProteinQ8N9N5 (Uniprot-TrEMBL)
Me2-K370,K382-TP53 TetramerComplexR-HSA-3222245 (Reactome)
Me2K-370,382-TP53 ProteinP04637 (Uniprot-TrEMBL)
PHF20 ProteinQ9BVI0 (Uniprot-TrEMBL)
PHF20:Me2-K370,K382-TP53 TetramerComplexR-HSA-3222249 (Reactome)
PHF20ProteinQ9BVI0 (Uniprot-TrEMBL)
POU4F1 ProteinQ01851 (Uniprot-TrEMBL)
POU4F1ProteinQ01851 (Uniprot-TrEMBL)
POU4F2 ProteinQ12837 (Uniprot-TrEMBL)
POU4F2ProteinQ12837 (Uniprot-TrEMBL)
PPP1R13B ProteinQ96KQ4 (Uniprot-TrEMBL)
PPP1R13B,TP53BP2ComplexR-HSA-6799786 (Reactome)
PPP1R13L ProteinQ8WUF5 (Uniprot-TrEMBL)
PPP1R13LProteinQ8WUF5 (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).

TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Regulates

Transcription of

Cell Cycle Genes		PathwayR-HSA-6791312 (Reactome) Under a variety of stress conditions, TP53 (p53), stabilized by stress-induced phosphorylation at least on S15 and S20 serine residues, can induce the transcription of genes involved in cell cycle arrest. Cell cycle arrest provides cells an opportunity to repair the damage before division, thus preventing the transmission of genetic errors to daughter cells. In addition, it allows cells to attempt a recovery from the damage and survive, preventing premature cell death.

TP53 controls transcription of genes involved in both G1 and G2 cell cycle arrest. The most prominent TP53 target involved in G1 arrest is the inhibitor of cyclin-dependent kinases CDKN1A (p21). CDKN1A is one of the earliest genes induced by TP53 (El-Deiry et al. 1993). CDKN1A binds and inactivates CDK2 in complex with cyclin A (CCNA) or E (CCNE), thus preventing G1/S transition (Harper et al. 1993). Nevertheless, under prolonged stress, the cell destiny may be diverted towards an apoptotic outcome. For instance, in case of an irreversible damage, TP53 can induce transcription of an RNA binding protein PCBP4, which can bind and destabilize CDKN1A mRNA, thus alleviating G1 arrest and directing the affected cell towards G2 arrest and, possibly, apoptosis (Zhu and Chen 2000, Scoumanne et al. 2011). Expression of E2F7 is directly induced by TP53. E2F7 contributes to G1 cell cycle arrest by repressing transcription of E2F1, a transcription factor that promotes expression of many genes needed for G1/S transition (Aksoy et al. 2012, Carvajal et al. 2012). ARID3A is a direct transcriptional target of TP53 (Ma et al. 2003) that may promote G1 arrest by cooperating with TP53 in induction of CDKN1A transcription (Lestari et al. 2012). However, ARID3A may also promote G1/S transition by stimulating transcriptional activity of E2F1 (Suzuki et al. 1998, Peeper et al. 2002).

TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014).

Several direct transcriptional targets of TP53 are involved in cell cycle arrest but their mechanism of action is still unknown. BTG2 is induced by TP53, leading to cessation of cellular proliferation (Rouault et al. 1996, Duriez et al. 2002). BTG2 binds to the CCR4-NOT complex and promotes mRNA deadenylation activity of this complex. Interaction between BTG2 and CCR4-NOT is needed for the antiproliferative activity of BTG2, but the underlying mechanism has not been elucidated (Rouault et al. 1998, Mauxion et al. 2008, Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012). Two polo-like kinases, PLK2 and PLK3, are direct transcriptional targets of TP53. TP53-mediated induction of PLK2 may be important for prevention of mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is involved in the regulation of centrosome duplication through phosphorylation of centrosome-related proteins CENPJ (Chang et al. 2010) and NPM1 (Krause and Hoffmann 2010). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006). Induction of PLK3 transcription by TP53 (Jen and Cheung 2005) may be important for coordination of M phase events through PLK3-mediated nuclear accumulation of CDC25C (Bahassi et al. 2004). RGCC is induced by TP53 and implicated in cell cycle regulation, possibly through its association with PLK1 (Saigusa et al. 2007). PLAGL1 (ZAC1) is a zinc finger protein directly transcriptionally induced by TP53 (Rozenfeld-Granot et al. 2002). PLAGL1 expression is frequently lost in cancer (Varrault et al. 1998) and PLAGL1 has been implicated in both cell cycle arrest and apoptosis (Spengler et al. 1997), but its mechanism of action remains unknown.

The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of CDKN1A and SFN (14-3-3 sigma) transcription (Das et al. 2007).

For a review of the role of TP53 in cell cycle arrest and cell cycle transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

TP53 Regulates

Transcription of

Cell Death Genes		PathwayR-HSA-5633008 (Reactome) The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress.
Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010).

TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).

It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).

TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available.

Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome.

TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013).


For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

TP53 TetramerComplexR-HSA-3209194 (Reactome)
TP53:BANPComplexR-HSA-3221977 (Reactome)
TP53BP2 ProteinQ13625 (Uniprot-TrEMBL)
TP63 ProteinQ9H3D4 (Uniprot-TrEMBL)
TP73 ProteinO15350 (Uniprot-TrEMBL)
ZNF385A Gene ProteinENSG00000161642 (Ensembl)
ZNF385A GeneGeneProductENSG00000161642 (Ensembl)
ZNF385A ProteinQ96PM9 (Uniprot-TrEMBL)
ZNF385AProteinQ96PM9 (Uniprot-TrEMBL)
p-S15,S20-TP53 Tetramer:POU4F1ComplexR-HSA-6804394 (Reactome)
p-S15,S20-TP53 Tetramer:POU4F2ComplexR-HSA-6804423 (Reactome)
p-S15,S20-TP53

Tetramer:ZNF385A

Gene		ComplexR-HSA-6803418 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AComplexR-HSA-6803718 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15,S20-TP53,TP63,TP73ComplexR-HSA-6798076 (Reactome)
p-S291-PHF20ProteinQ9BVI0 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ArrowR-HSA-6799777 (Reactome)
(p-S15,S20-TP53,TP63,TP73):PPP1R13LArrowR-HSA-6799761 (Reactome)
ADPArrowR-HSA-6805785 (Reactome)
ATPR-HSA-6805785 (Reactome)
Active AKTmim-catalysisR-HSA-6805785 (Reactome)
BANPR-HSA-3221982 (Reactome)
Me2-K370,K382-TP53 TetramerR-HSA-3222259 (Reactome)
PHF20:Me2-K370,K382-TP53 TetramerArrowR-HSA-3222259 (Reactome)
PHF20R-HSA-3222259 (Reactome)
PHF20R-HSA-6805785 (Reactome)
POU4F1R-HSA-6804402 (Reactome)
POU4F2R-HSA-6804425 (Reactome)
PPP1R13B,TP53BP2R-HSA-6799777 (Reactome)
PPP1R13LR-HSA-6799761 (Reactome)
R-HSA-3221982 (Reactome) BANP (SMAR1) binds TP53 (p53) and is implicated in both positive (Kaul et al. 2003, Jalota et al. 2005) and negative regulation of TP53 transcriptional activity (Pavithra et al. 2009, Sinha et al. 2010).
R-HSA-3222259 (Reactome) PHF20 binds TP53 (p53) dimethylated at lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s). PHF20 binding interferes with MDM2 binding to TP53, thus resulting in TP53 stabilization (Cui et al. 2012).
R-HSA-6799761 (Reactome) PPP1R13L encodes the inhibitory member of the ASPP family - iASPP. PPP1R13L binds TP53 (p53) and inhibits its pro-apoptotic transcriptional activity. PPP1R13L cooperates with RAS, adenovirus protein E1A and the human papillomavirus protein E7 in cell transformation (Bergamaschi et al. 2003, Wilson et al. 2014). The C-terminus of PPP1R13L consists of four ankyrin repeats and an SH3 domain that form a p53-binding site. PPP1R13L binds the DNA binding site of TP53 (Robinson et al. 2008). PPP1R13L also interacts with p53 family members TP63 (p63) and TP73 (p73) (Robinson et al. 2008) and inhibits their pro-apoptotic transcriptional activity (Cai et al. 2012).
R-HSA-6799777 (Reactome) TP53 (p53) forms a complex with PPP1R13B (ASPP1) or TP53BP2 (ASPP2). This interaction involves the DNA binding domain of TP53 and the C-terminus of ASSP proteins (Samuels-Lev et al. 2001, Patel et al. 2008). ASPP proteins can also form a complex with p53 family members TP63 (p63) and TP73 (p73) (Robinson et al. 2008, Patel et al. 2008). ASPP proteins enhance the binding of p53 family members to promoters of pro-apoptotic genes and promote their transcription, but do not affect the transcription of cell cycle regulators. ASPP proteins are frequently down-regulated in breast cancers that express wild-type TP53 (Samuels-Lev et al. 2001, Bergamaschi et al. 2004).
R-HSA-6803425 (Reactome) TP53 (p53) binds to at least one of the three putative p53 response elements in the promoter of the human ZNF385A (HZF) gene (Das et al. 2007). In the mouse Znf385a gene, the p53 response element is in the first intron and also binds Tp53 (Sugimoto et al. 2006).
R-HSA-6803437 (Reactome) Binding of TP53 (p53) to the p53 response element(s) in the promoter of the ZNF385A (HZF) gene stimulates ZNF385A transcription (Das et al. 2007). TP53-mediated induction of ZNF385A is conserved in mouse (Sugimoto et al. 2006, Das et al. 2007).
R-HSA-6803719 (Reactome) ZNF385A (HZF) forms a complex with TP53 (p53), interacting with the DNA binding domain of TP53. The complex of TP53 and ZNF385A associates with p53 response elements of cell cycle arrest genes, such as CDKN1A (p21) and stimulates their transcription. Under prolonged stress, ZNF385A undergoes ubiquitination and proteasome-mediated degradation, which coincides with expression of TP53-regulated pro-apoptotic genes (Das et al. 2007).
R-HSA-6804402 (Reactome) TP53 (p53) forms a complex with a transcription factor POU4F1 (BRN3A). This interaction involves the POU domain of POU4F1. Binding of TP53 to POU4F1 modulates the transcriptional activity of both proteins, but the exact mechanism has not been elucidated. TP53 inhibits POU4F1-mediated induction of BCL2 transcription (Budhram-Mahadeo et al. 1999). POU4F1 inhibits TP53-mediated induction of BAX and NOXA, but enhances TP53-mediated induction of CDKN1A (p21) (Budhram-Mahadeo et al. 2002, Hudson et al. 2005).
R-HSA-6804425 (Reactome) POU4F2 (BRN3B), similarly to POU4F1 (BRN3A), forms a complex with TP53 (p53). The interaction involves the POU domain of POU4F2 and the DNA binding domain of TP53. In contrast to POU4F1, binding of POU4F2 to TP53 enhances TP53-mediated transcriptional induction of pro-apoptotic targets such as BAX (Budhram-Mahadeo et al. 2006), NOXA and PUMA (Budhram-Mahadeo et al. 2014). The pro-apoptotic action of the complex of POU4F2 and TP53 may control the fate of cardiomyocytes in injured heart (Budhram-Mahadeo et al. 2014).
R-HSA-6805785 (Reactome) AKT phosphorylates PHF20 on serine residue S291 (Park et al. 2012, Li et al. 2013), triggering PHF20 translocation to the cytosol (Park et al. 2012).
R-HSA-6805792 (Reactome) PHF20 phosphorylated at serine S291 by AKT (Park et al. 2012, Li et al. 2013) translocates to the cytosol (Park et al. 2012). AKT thus prevents PHF20-mediated stimulation of TP53 (p53) activity (Park et al. 2012, Li et al. 2013).
TP53 TetramerR-HSA-3221982 (Reactome)
TP53:BANPArrowR-HSA-3221982 (Reactome)
ZNF385A GeneR-HSA-6803425 (Reactome)
ZNF385A GeneR-HSA-6803437 (Reactome)
ZNF385AArrowR-HSA-6803437 (Reactome)
ZNF385AR-HSA-6803719 (Reactome)
p-S15,S20-TP53 Tetramer:POU4F1ArrowR-HSA-6804402 (Reactome)
p-S15,S20-TP53 Tetramer:POU4F2ArrowR-HSA-6804425 (Reactome)
p-S15,S20-TP53

Tetramer:ZNF385A

Gene		ArrowR-HSA-6803425 (Reactome)
p-S15,S20-TP53

Tetramer:ZNF385A

Gene		ArrowR-HSA-6803437 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AArrowR-HSA-6803719 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803425 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803719 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804402 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804425 (Reactome)
p-S15,S20-TP53,TP63,TP73R-HSA-6799761 (Reactome)
p-S15,S20-TP53,TP63,TP73R-HSA-6799777 (Reactome)
p-S291-PHF20ArrowR-HSA-6805785 (Reactome)
p-S291-PHF20ArrowR-HSA-6805792 (Reactome)
p-S291-PHF20R-HSA-6805792 (Reactome)

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