Pathway Human Homo sapiens

Oncogene Induced Senescence

R-HSA-2559585 in Reactome release 97: under Cellular Senescence, with 37 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-2559585 (mouse), R-RNO-2559585 (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-2559585.8
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2013-09-18
Last updated: 2019-12-10
Events inside: 19, counted from the record

Oncogene-induced senescence (OIS) is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16INK4A and p14ARF. p16INK4A and p14ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15INK4B, together with p16INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).

MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16INK4A transcription (Ohtani et al. 2004).

Transcription of p14ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14ARF promoter (Parisi et al. 2002).

Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.

While OIS has been studied to considerable detail in cultured cells, establishment of in vivo role of OIS has been difficult due to lack of specific biomarkers and its interconnectedness with other senescence pathways (Baek and Ryeom 2017, reviewed in Sharpless and Sherr 2015).

Literature Reactome attaches

p16(INK4a) translation suppressed by miR-24PLoS ONE, 2008, vol. 3, p. e1864PubMed 18365017
Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma developmentBMC Cancer, 2012, vol. 12, p. 69PubMed 22336108
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4Nature, 1993, vol. 366, p. 704-7PubMed 8259215
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
Mdm2 association with p53 targets its ubiquitinationOncogene, 1998, vol. 17, p. 2543-7PubMed 9824166
The p53-mdm-2 autoregulatory feedback loopGenes Dev., 1993, vol. 7, p. 1126-32PubMed 8319905
Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53J. Biol. Chem., 2000, vol. 275, p. 8945-51PubMed 10722742

Reactome's record lists 10 orthologous events, R-MMU-2559585 (Mus musculus), R-RNO-2559585 (Rattus norvegicus) among the species this site serves, and 8 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"Oncogene Induced Senescence". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-2559585 with StableID: R-HSA-2559585.8 (accessed 2026-10-01 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 37 genes in this human pathway; showing 1 to 37, in pages of 100, sorted by symbol for reading. The order carries no ranking. 2 of the rows shown carry an id the identity file does not name, kept as the source wrote it.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAGO1	AuthorityHGNC:3262	Mapping file id26523 NCBI file	EvidenceTAS
GeneAGO3	AuthorityHGNC:18421	Mapping file id192669 NCBI file	EvidenceTAS
GeneAGO4	AuthorityHGNC:18424	Mapping file id192670 NCBI file	EvidenceTAS
GeneCDK4	AuthorityHGNC:1773	Mapping file id1019 NCBI file	EvidenceTAS
GeneCDK6	AuthorityHGNC:1777	Mapping file id1021 NCBI file	EvidenceTAS
GeneCDKN2A	AuthorityHGNC:1787	Mapping file id1029 NCBI file	EvidenceTAS
GeneCDKN2B	AuthorityHGNC:1788	Mapping file id1030 NCBI file	EvidenceTAS
GeneCDKN2C	AuthorityHGNC:1789	Mapping file id1031 NCBI file	EvidenceTAS
GeneCDKN2D	AuthorityHGNC:1790	Mapping file id1032 NCBI file	EvidenceTAS
GeneE2F1	AuthorityHGNC:3113	Mapping file id1869 NCBI file	EvidenceTAS
GeneE2F2	AuthorityHGNC:3114	Mapping file id1870 NCBI file	EvidenceTAS
GeneE2F3	AuthorityHGNC:3115	Mapping file id1871 NCBI file	EvidenceTAS
GeneERF	AuthorityHGNC:3444	Mapping file id2077 NCBI file	EvidenceIEA, TAS
GeneETS1	AuthorityHGNC:3488	Mapping file id2113 NCBI file	EvidenceTAS
GeneETS2	AuthorityHGNC:3489	Mapping file id2114 NCBI file	EvidenceTAS
GeneID1	AuthorityHGNC:5360	Mapping file id3397 NCBI file	EvidenceTAS
GeneMAPK1	AuthorityHGNC:6871	Mapping file id5594 NCBI file	EvidenceIEA, TAS
GeneMAPK3	AuthorityHGNC:6877	Mapping file id5595 NCBI file	EvidenceIEA, TAS
GeneMDM2	AuthorityHGNC:6973	Mapping file id4193 NCBI file	EvidenceTAS
GeneMDM4	AuthorityHGNC:6974	Mapping file id4194 NCBI file	EvidenceTAS
GeneMIR24-1	AuthorityHGNC:31607	Mapping file idENSG00000284459 Ensembl file	EvidenceTAS
GeneMIR24-2	AuthorityHGNC:31608	Mapping file idENSG00000284387 Ensembl file	EvidenceTAS
GeneMOV10	AuthorityHGNC:7200	Mapping file id4343 NCBI file	EvidenceTAS
GeneRB1	AuthorityHGNC:9884	Mapping file id5925 NCBI file	EvidenceTAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneSP1	AuthorityHGNC:11205	Mapping file id6667 NCBI file	EvidenceTAS
GeneTFDP1	AuthorityHGNC:11749	Mapping file id7027 NCBI file	EvidenceTAS
GeneTFDP2	AuthorityHGNC:11751	Mapping file id7029 NCBI file	EvidenceTAS
GeneTNRC6A	AuthorityHGNC:11969	Mapping file id27327 NCBI file	EvidenceTAS
GeneTNRC6B	AuthorityHGNC:29190	Mapping file id23112 NCBI file	EvidenceTAS
GeneTNRC6C	AuthorityHGNC:29318	Mapping file id57690 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
Geneno symbol in the identity file	Authoritynone	Mapping file idNM_000077.4 as written	EvidenceTAS
Geneno symbol in the identity file	Authoritynone	Mapping file idNM_058195.3 as written	EvidenceTAS

Evidence codes on this page: IEA, 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

Cellular SenescenceR-HSA-2559583200 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.