Pathway Human Homo sapiens

Regulation of TP53 Degradation

R-HSA-6804757 in Reactome release 97: under Regulation of TP53 Expression and Degradation, with 36 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-6804757 (mouse), R-RNO-6804757 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-6804757.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2016-03-23
Last updated: 2019-06-12
Events inside: 30, counted from the record

In unstressed cells, TP53 (p53) has a short half-life as it undergoes rapid ubiquitination and proteasome-mediated degradation. The E3 ubiquitin ligase MDM2, which is a transcriptional target of TP53, plays the main role in TP53 protein down-regulation (Wu et al. 1993). MDM2 forms homodimers and homo-oligomers, but also functions as a heterodimer/hetero-oligomer with MDM4 (MDMX) (Sharp et al. 1999, Cheng et al. 2011, Huang et al. 2011, Pant et al. 2011). The heterodimers of MDM2 and MDM4 may be especially important for downregulation of TP53 during embryonic development (Pant et al. 2011).

The nuclear localization of MDM2 is positively regulated by AKT- or SGK1- mediated phosphorylation (Mayo and Donner 2001, Zhou et al. 2001, Amato et al. 2009, Lyo et al. 2010). Phosphorylation of MDM2 by CDK1 or CDK2 decreases affinity of MDM2 for TP53 (Zhang and Prives 2001). ATM and CHEK2 kinases, activated by double strand DNA breaks, phosphorylate TP53, reducing its affinity for MDM2 (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998, Chehab et al. 1999, Chehab et al. 2000). At the same time, ATM phosphorylates MDM2, preventing MDM2 dimerization (Cheng et al. 2009, Cheng et al. 2011). Both ATM and CHEK2 phosphorylate MDM4, triggering MDM2-mediated ubiquitination of MDM4 (Chen et al. 2005, Pereg et al. 2005). Cyclin G1 (CCNG1), transcriptionally induced by TP53, targets the PP2A phosphatase complex to MDM2, resulting in dephosphorylation of MDM2 at specific sites, which can have either a positive or a negative impact on MDM2 function (Okamoto et al. 2002).

In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007).

In addition to ubiquitinating MDM4 (Pereg et al. 2005), MDM2 can also undergo auto-ubiquitination (Fang et al. 2000). MDM2 and MDM4 can be deubiquitinated by the ubiquitin protease USP2 (Stevenson et al. 2007, Allende-Vega et al. 2010). The ubiquitin protease USP7 can deubiquitinate TP53, but in the presence of DAXX deubiquitinates MDM2 (Li et al. 2002, Sheng et al. 2006, Tang et al. 2006).

The tumor suppressor p14-ARF, expressed from the CDKN2A gene in response to oncogenic or oxidative stress, forms a tripartite complex with MDM2 and TP53, sequesters MDM2 from TP53, and thus prevents TP53 degradation (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005).

For review of this topic, please refer to Kruse and Gu 2009.

Literature Reactome attaches

The p53-mdm-2 autoregulatory feedback loopGenes Dev., 1993, vol. 7, p. 1126-32PubMed 8319905
ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathwaysCell, 1998, vol. 92, p. 725-34PubMed 9529249
Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factorsBiochem. Biophys. Res. Commun., 2002, vol. 291, p. 1138-45PubMed 11883935
MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1J. Biol. Chem., 2005, vol. 280, p. 5178-87PubMed 15563468
Cyclin G recruits PP2A to dephosphorylate Mdm2Mol. Cell, 2002, vol. 9, p. 761-71PubMed 11983168
CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradationJ. Biol. Chem., 2007, vol. 282, p. 3273-81PubMed 17121812
Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damageProc Natl Acad Sci U S A, 2005, vol. 102, p. 5056-61

Reactome's record lists 13 orthologous events, R-RNO-6804757 (Rattus norvegicus), R-MMU-6804757 (Mus musculus) among the species this site serves, and 11 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Regulation of TP53 Degradation". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-6804757 with StableID: R-HSA-6804757.3 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 36 genes in this human pathway; showing 1 to 36, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAKT1	AuthorityHGNC:391	Mapping file id207 NCBI file	EvidenceTAS
GeneAKT2	AuthorityHGNC:392	Mapping file id208 NCBI file	EvidenceTAS
GeneAKT3	AuthorityHGNC:393	Mapping file id10000 NCBI file	EvidenceTAS
GeneATM	AuthorityHGNC:795	Mapping file id472 NCBI file	EvidenceTAS
GeneCCNA1	AuthorityHGNC:1577	Mapping file id8900 NCBI file	EvidenceTAS
GeneCCNA2	AuthorityHGNC:1578	Mapping file id890 NCBI file	EvidenceTAS
GeneCCNG1	AuthorityHGNC:1592	Mapping file id900 NCBI file	EvidenceTAS
GeneCDK1	AuthorityHGNC:1722	Mapping file id983 NCBI file	EvidenceTAS
GeneCDK2	AuthorityHGNC:1771	Mapping file id1017 NCBI file	EvidenceTAS
GeneCDKN2A	AuthorityHGNC:1787	Mapping file id1029 NCBI file	EvidenceTAS
GeneCHEK2	AuthorityHGNC:16627	Mapping file id11200 NCBI file	EvidenceTAS
GeneDAXX	AuthorityHGNC:2681	Mapping file id1616 NCBI file	EvidenceTAS
GeneMAPKAP1	AuthorityHGNC:18752	Mapping file id79109 NCBI file	EvidenceTAS
GeneMDM2	AuthorityHGNC:6973	Mapping file id4193 NCBI file	EvidenceTAS
GeneMDM4	AuthorityHGNC:6974	Mapping file id4194 NCBI file	EvidenceTAS
GeneMLST8	AuthorityHGNC:24825	Mapping file id64223 NCBI file	EvidenceTAS
GeneMTOR	AuthorityHGNC:3942	Mapping file id2475 NCBI file	EvidenceTAS
GenePDPK1	AuthorityHGNC:8816	Mapping file id5170 NCBI file	EvidenceTAS
GenePHF20	AuthorityHGNC:16098	Mapping file id51230 NCBI file	EvidenceTAS
GenePPP2CA	AuthorityHGNC:9299	Mapping file id5515 NCBI file	EvidenceTAS
GenePPP2CB	AuthorityHGNC:9300	Mapping file id5516 NCBI file	EvidenceTAS
GenePPP2R1A	AuthorityHGNC:9302	Mapping file id5518 NCBI file	EvidenceTAS
GenePPP2R1B	AuthorityHGNC:9303	Mapping file id5519 NCBI file	EvidenceTAS
GenePPP2R5C	AuthorityHGNC:9311	Mapping file id5527 NCBI file	EvidenceTAS
GenePRR5	AuthorityHGNC:31682	Mapping file id55615 NCBI file	EvidenceTAS
GeneRFFL	AuthorityHGNC:24821	Mapping file id117584 NCBI file	EvidenceTAS
GeneRICTOR	AuthorityHGNC:28611	Mapping file id253260 NCBI file	EvidenceTAS
GeneRNF34	AuthorityHGNC:17297	Mapping file id80196 NCBI file	EvidenceTAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneSGK1	AuthorityHGNC:10810	Mapping file id6446 NCBI file	EvidenceTAS
GeneTP53	AuthorityHGNC:11998	Mapping file id7157 NCBI file	EvidenceTAS
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceTAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceTAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceTAS
GeneUSP2	AuthorityHGNC:12618	Mapping file id9099 NCBI file	EvidenceTAS
GeneUSP7	AuthorityHGNC:12630	Mapping file id7874 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Regulation of TP53 Expression and DegradationR-HSA-680600337 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.