TP53 Regulates Transcription of Cell Death Genes (Homo sapiens)

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1, 3, 4, 8, 10...9133, 83, 87105278411151, 10, 32, 7317, 249, 10251, 593429, 60, 80, 87, 9942, 88, 936713, 16, 8616, 8635, 49, 54, 74, 924533, 87, 90983440, 558, 7833, 87, 9024, 101981, 10, 26, 32, 73...33, 83, 87117, 7124917510556, 60368, 63, 70, 7847, 5215, 794, 57, 60, 1041621, 53, 82, 85, 100...45, 81, 9710249, 8925, 4753, 82, 1005191614, 72, 756722, 3451, 59, 61, 684, 57, 60, 10444, 864229, 60, 80, 87, 99365, 23, 10256, 6040, 554646711927, 31, 41, 85, 100nucleoplasmmitochondrial matrixcytosolendosome membranemitochondrionBIRC5TP53INP1 GeneTP53I3 DimerTP53AIP1 Gene p-S15,S20-TP53Tetramer:TRIAP1Gene(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BAX Genep-S15,S20-TP53 p-S15,S20-TP53TetramerCASP10 Gene TP53AIP1 Genep-S15,S20-TP53:NLRC4GenePRELID3A p-S15,S20-TP53 p-S15,S20-TP53Tetramer:CASP10GeneIron uptake andtransportTP63 STEAP3CASP1 GeneRABGGTB TNFRSF10D Gene STEAP3 Genep-S15,S20-TP53 CRADDTP53I3 p-S15,S20-TP53Tetramer:PIDD1 GenePPP1R13B p-S15,S20-TP53Tetramer:BID Genep-S15,S20-TP53Tetramer:BCL6 GeneInterleukin-1processingp-S15,S20-TP53 CASP2(2-452) TP53I3TP63 p-S15,S20-TP53Tetramer:BCL2L14Genep-S15,S20-TP53 p-S15,S20-TP53Tetramer:TP53INP1GenePERP Genep-S15,S20-TP53 (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 Genep-S15,S20-TP53 p-S15,S20-TP53 p-S15,S20-TP53Tetramer:NDRG1 GeneFAS GeneO2.-TNFRSF10C TP53BP2 NLRC4 GeneTP53BP2 IGFBP3 Gene PERPTP63 TP73 p-S15,S20-TP53 CREBBPp-S15,S20,S46-TP53 RGGT:CHMAIFM2 Genep-T788-PIDD1 p-S15,S20-TP53 O2RABGGTA Genep-S15,S20-TP53 Regulation ofInsulin-like GrowthFactor (IGF)transport anduptake byInsulin-like GrowthFactor BindingProteins (IGFBPs)ZNF420:TP53AIP1 GeneBID GeneTP73 NADPHBAXCASP6 Gene BNIP3LApoptotic executionphaseADPp-S15,S20,S46-TP53TetramerPAPMAIP1 Gene TMEM219TNFRSF10A Gene BBC3 Gene p-S15,S20-TP53Tetramer:TNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10D Genesp-S15,S20-TP53 p-T788-PIDD1BCL6 GeneTNFRSF10A Gene TP53BP2 TNFRSF10D Gene TRIAP1 IGFBP3 PPP1R13B p-S1981,Ac-K3016-ATMp-S15,S20-TP53Tetramer:CASP6 GeneBIRC5 Gene p-S15,S20-TP53 RABGGTB FAS Gene AIFM2 Gene TP63 Intrinsic Pathwayfor ApoptosisBAX gene PMAIP1p-S15,S20-TP53 p-S15,S20-TP53 TNFRSF10B p-S15,S20-TP53 PRELID1 TP73 PERP Gene TP73 TRIAP1CHM CASP1 Gene BNIP3L Genep-S15,S20-TP53Tetramer:RABGGTAGeneTP73 CASP1(1-404)TNFRSF10B Gene TP63 p-S15,S20-TP53 NDRG1 Gene 1,2-NaphthoquinoneATPFasL/ CD95LsignalingBCL6 Gene p-S15,S20-TP53 (p-S15,S20-TP53,TP63):PERP GeneTNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10DTP73 ZNF420PIDD1 Genep-S15,S20-TP53Tetramer:APAF1 Genep-S15,S20,S46-TP53Tetramer:TP53AIP1GeneInnate Immune SystemTP73 ADPTP53BP2 CREBBP TP53INP1 Gene p-S15,S20-TP53 APAF1 geneCRADD p-S15,S20-TP53Tetramer:PMAIP1Genep-S15,S20,S46-TP53 PRELID3A IGFBP3:TMEM219BCL2L14 Gene TNFRSF10A,TNFRSF10B,TNFRSF10C,TNFRSF10D GenesRABGGTATRAIL signalingBBC3 GeneCASP10 GeneAIFM2semiquinonep-S15,S20-TP53,TP63,TP73RGGTRABGGTA (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):FAS GeneTRIAP1:PRELID1,PRELID3ATNFRSF10C Gene BNIP3L Gene CASP2(170-325)TNFRSF10A p-S15,S20-TP53 RABGGTA Gene p-S15,S20-TP53Tetramer:AIFM2 GeneNDRG1 GeneATPIGFBP3p-S15,S20-TP53 p-S15,S20-TP53Tetramer:BIRC5 GeneTP53INP1PRELID1, PRELID3Ap-S15,S20-TP53 CASP2(348-452)PPP1R13B BCL6PAp-S15,S20-TP53 TP53I3 Gene(p-S15,S20-TP53,TP63,TP73):CASP1 GeneBIRC5 GeneRegulation of TP53ActivityBCL2L14 Genep-S15,S20-TP53 TP53BP2 PMAIP1 GeneTMEM219 NADP+TRIAP1 Genep-T788-PIDD1STEAP3 Gene CRADD TNFRSF10D PIDDosome:CASP2(2-452)p-S15,S20-TP53 BBC3CHMNLRC4 Gene CASP2(2-452)p-S15,S20-TP53Tetramer:STEAP3GeneCASP6 GeneRABGGTB(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):TP53I3 Genep-S15,S20-TP53,TP63TP53I3 Gene TNFRSF10C Gene ZNF420 CASP6 (1-293)FASp-S15,S20-TP53Tetramer:CREBBP:BNIP3L GeneTP63 PRELID1 (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)CASP10(1-521)TNFRSF10B Gene TP53AIP1p-S15,S20-TP53 BNIP3L p-T788-PIDD1 p-S15,S20-TP53 PIDD1STEAP3:BNIP3LH+PPP1R13B STEAP3 PIDD1 Gene TRIAP1 Gene APAF1 gene TP53AIP1 Gene IGFBP3 GeneTP63 p-S15,S20-TP53 p-S15,S20-TP53Tetramer:IGFBP3GenePIDDosomeRABGGTA p-S15,S20-TP53 APAF1BID(1-195)NDRG1p-S68-ZNF420BID Gene BAX geneTP63 NLRC4BCL2L14PPP1R13B TP63 517, 243655758, 782, 38, 95276, 18, 28, 764, 10451, 592467779146428349861153, 82, 100102651054756, 6084349029, 9943, 58, 6449159820, 30, 37, 39, 50...851213, 16, 861, 10, 32, 73714519


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).<p>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).<p>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.<p>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.<p>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).<p>
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. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 5633008
Reactome version: 66
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Reactome Author: Orlic-Milacic, Marija

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101592view11:46, 1 November 2018ReactomeTeamreactome version 66
101128view21:31, 31 October 2018ReactomeTeamreactome version 65
100656view20:05, 31 October 2018ReactomeTeamreactome version 64
100206view16:50, 31 October 2018ReactomeTeamreactome version 63
99757view15:16, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99319view12:47, 31 October 2018ReactomeTeamreactome version 62
93790view13:36, 16 August 2017ReactomeTeamreactome version 61
93324view11:20, 9 August 2017ReactomeTeamreactome version 61
88393view15:16, 4 August 2016FehrhartOntology Term : 'cell death pathway' added !
88392view15:15, 4 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86411view09:17, 11 July 2016ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
(p-S15,S20-TP53,TP63):PERP GeneComplexR-HSA-6800835 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BAX GeneComplexR-HSA-3700978 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneComplexR-HSA-4331345 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):FAS GeneComplexR-HSA-6799810 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):TP53I3 GeneComplexR-HSA-6799461 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ComplexR-HSA-6799788 (Reactome)
(p-S15,S20-TP53,TP63,TP73):CASP1 GeneComplexR-HSA-6798078 (Reactome)
1,2-NaphthoquinoneMetaboliteCHEBI:34055 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
AIFM2 Gene ProteinENSG00000042286 (Ensembl)
AIFM2 GeneGeneProductENSG00000042286 (Ensembl)
AIFM2ProteinQ9BRQ8 (Uniprot-TrEMBL)
APAF1 gene ProteinENSG00000120868 (Ensembl)
APAF1 geneGeneProductENSG00000120868 (Ensembl)
APAF1ProteinO14727 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Apoptotic execution phasePathwayR-HSA-75153 (Reactome) In the execution phase of apoptosis, effector caspases cleave vital cellular proteins leading to the morphological changes that characterize apoptosis. These changes include destruction of the nucleus and other organelles, DNA fragmentation, chromatin condensation, cell shrinkage and cell detachment and membrane blebbing (reviewed in Fischer et al., 2003).
BAX gene ProteinENSG00000087088 (Ensembl)
BAX geneGeneProductENSG00000087088 (Ensembl)
BAXProteinQ07812 (Uniprot-TrEMBL)
BBC3 Gene ProteinENSG00000105327 (Ensembl)
BBC3 GeneGeneProductENSG00000105327 (Ensembl)
BBC3ProteinQ9BXH1 (Uniprot-TrEMBL)
BCL2L14 Gene ProteinENSG00000121380 (Ensembl)
BCL2L14 GeneGeneProductENSG00000121380 (Ensembl)
BCL2L14ProteinQ9BZR8 (Uniprot-TrEMBL)
BCL6 Gene ProteinENSG00000113916 (Ensembl)
BCL6 GeneGeneProductENSG00000113916 (Ensembl)
BCL6ProteinP41182 (Uniprot-TrEMBL)
BID Gene ProteinENSG00000015475 (Ensembl)
BID GeneGeneProductENSG00000015475 (Ensembl)
BID(1-195)ProteinP55957 (Uniprot-TrEMBL)
BIRC5 Gene ProteinENSG00000089685 (Ensembl)
BIRC5 GeneGeneProductENSG00000089685 (Ensembl)
BIRC5ProteinO15392 (Uniprot-TrEMBL)
BNIP3L Gene ProteinENSG00000104765 (Ensembl)
BNIP3L GeneGeneProductENSG00000104765 (Ensembl)
BNIP3L ProteinO60238 (Uniprot-TrEMBL)
BNIP3LProteinO60238 (Uniprot-TrEMBL)
CASP1 Gene ProteinENSG00000137752 (Ensembl)
CASP1 GeneGeneProductENSG00000137752 (Ensembl)
CASP1(1-404)ProteinP29466 (Uniprot-TrEMBL)
CASP10 Gene ProteinENSG00000003400 (Ensembl)
CASP10 GeneGeneProductENSG00000003400 (Ensembl)
CASP10(1-521)ProteinQ92851 (Uniprot-TrEMBL)
CASP2(170-325)ProteinP42575 (Uniprot-TrEMBL)
CASP2(2-452) ProteinP42575 (Uniprot-TrEMBL)
CASP2(2-452)ProteinP42575 (Uniprot-TrEMBL)
CASP2(348-452)ProteinP42575 (Uniprot-TrEMBL)
CASP6 (1-293)ProteinP55212 (Uniprot-TrEMBL)
CASP6 Gene ProteinENSG00000138794 (Ensembl)
CASP6 GeneGeneProductENSG00000138794 (Ensembl)
CHM ProteinP24386 (Uniprot-TrEMBL)
CHMProteinP24386 (Uniprot-TrEMBL)
CRADD ProteinP78560 (Uniprot-TrEMBL)
CRADDProteinP78560 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
FAS Gene ProteinENSG00000026103 (Ensembl)
FAS GeneGeneProductENSG00000026103 (Ensembl)
FASProteinP25445 (Uniprot-TrEMBL)
FasL/ CD95L signalingPathwayR-HSA-75157 (Reactome) The Fas family of cell surface receptors initiate the apototic pathway through interaction with the external ligand, FasL. The cytoplasmic domain of Fas interacts with a number of molecules in the transduction of the external signal to the cytoplasmic side of the cell membrane. The most notable cytoplasmic domain is the Death Domain (DD) that is involved in recruiting the FAS-associating death domain-containing protein (FADD). This interaction drives downstream events.
H+MetaboliteCHEBI:15378 (ChEBI)
IGFBP3 Gene ProteinENSG00000146674 (Ensembl)
IGFBP3 GeneGeneProductENSG00000146674 (Ensembl)
IGFBP3 ProteinP17936 (Uniprot-TrEMBL)
IGFBP3:TMEM219ComplexR-HSA-6800024 (Reactome)
IGFBP3ProteinP17936 (Uniprot-TrEMBL)
Innate Immune SystemPathwayR-HSA-168249 (Reactome) Innate immunity encompases the nonspecific part of immunity tha are part of an individual's natural biologic makeup
Interleukin-1 processingPathwayR-HSA-448706 (Reactome) The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

Iron uptake and transportPathwayR-HSA-917937 (Reactome) The transport of iron between cells is mediated by transferrin. However, iron can also enter and leave cells not only by itself, but also in the form of heme and siderophores. When entering the cell via the main path (by transferrin endocytosis), its goal is not the (still elusive) chelated iron pool in the cytosol nor the lysosomes but the mitochondria, where heme is synthesized and iron-sulfur clusters are assembled (Kurz et al,2008, Hower et al 2009, Richardson et al 2010).
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NDRG1 Gene ProteinENSG00000104419 (Ensembl)
NDRG1 GeneGeneProductENSG00000104419 (Ensembl)
NDRG1ProteinQ92597 (Uniprot-TrEMBL)
NLRC4 Gene ProteinENSG00000091106 (Ensembl)
NLRC4 GeneGeneProductENSG00000091106 (Ensembl)
NLRC4ProteinQ9NPP4 (Uniprot-TrEMBL)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PAMetaboliteCHEBI:16337 (ChEBI)
PERP Gene ProteinENSG00000112378 (Ensembl)
PERP GeneGeneProduct