Pathway Human Homo sapiens

Oxidative Stress Induced Senescence

R-HSA-2559580 in Reactome release 97: under Cellular Senescence, with 128 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-2559580 (mouse), R-RNO-2559580 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

Scripts are off

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-2559580.8
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: 40, counted from the record

Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).

MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.

MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).

Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).

Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16INK4A and p14ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).

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

Genes Reactome places in this human pathway, page 1 of 2
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
GeneBMI1	AuthorityHGNC:1066	Mapping file id648 NCBI file	EvidenceTAS
GeneCBX2	AuthorityHGNC:1552	Mapping file id84733 NCBI file	EvidenceTAS
GeneCBX4	AuthorityHGNC:1554	Mapping file id8535 NCBI file	EvidenceTAS
GeneCBX6	AuthorityHGNC:1556	Mapping file id23466 NCBI file	EvidenceTAS
GeneCBX8	AuthorityHGNC:15962	Mapping file id57332 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
GeneCOMMD3-BMI1	AuthorityHGNC:48326	Mapping file id100532731 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
GeneEED	AuthorityHGNC:3188	Mapping file id8726 NCBI file	EvidenceTAS
GeneEZH2	AuthorityHGNC:3527	Mapping file id2146 NCBI file	EvidenceTAS
GeneFOS	AuthorityHGNC:3796	Mapping file id2353 NCBI file	EvidenceTAS
GeneH2AB1	AuthorityHGNC:22516	Mapping file id474382 NCBI file	EvidenceTAS
GeneH2AC14	AuthorityHGNC:4727	Mapping file id8331 NCBI file	EvidenceTAS
GeneH2AC18	AuthorityHGNC:4736	Mapping file id8337 NCBI file	EvidenceTAS
GeneH2AC19	AuthorityHGNC:29668	Mapping file id723790 NCBI file	EvidenceTAS
GeneH2AC20	AuthorityHGNC:4738	Mapping file id8338 NCBI file	EvidenceTAS
GeneH2AC4	AuthorityHGNC:4734	Mapping file id8335 NCBI file	EvidenceTAS
GeneH2AC6	AuthorityHGNC:4733	Mapping file id8334 NCBI file	EvidenceTAS
GeneH2AC7	AuthorityHGNC:4729	Mapping file id3013 NCBI file	EvidenceTAS
GeneH2AC8	AuthorityHGNC:4724	Mapping file id3012 NCBI file	EvidenceTAS
GeneH2AJ	AuthorityHGNC:14456	Mapping file id55766 NCBI file	EvidenceTAS
GeneH2AX	AuthorityHGNC:4739	Mapping file id3014 NCBI file	EvidenceTAS
GeneH2AZ2	AuthorityHGNC:20664	Mapping file id94239 NCBI file	EvidenceTAS
GeneH2BC1	AuthorityHGNC:18730	Mapping file id255626 NCBI file	EvidenceTAS
GeneH2BC10	AuthorityHGNC:4756	Mapping file id8346 NCBI file	EvidenceTAS
GeneH2BC11	AuthorityHGNC:4761	Mapping file id8970 NCBI file	EvidenceTAS
GeneH2BC12	AuthorityHGNC:13954	Mapping file id85236 NCBI file	EvidenceTAS
GeneH2BC12L	AuthorityHGNC:4762	Mapping file id54145 NCBI file	EvidenceTAS
GeneH2BC13	AuthorityHGNC:4748	Mapping file id8340 NCBI file	EvidenceTAS
GeneH2BC14	AuthorityHGNC:4750	Mapping file id8342 NCBI file	EvidenceTAS
GeneH2BC15	AuthorityHGNC:4749	Mapping file id8341 NCBI file	EvidenceTAS
GeneH2BC17	AuthorityHGNC:4758	Mapping file id8348 NCBI file	EvidenceTAS
GeneH2BC21	AuthorityHGNC:4760	Mapping file id8349 NCBI file	EvidenceTAS
GeneH2BC26	AuthorityHGNC:20514	Mapping file id128312 NCBI file	EvidenceTAS
GeneH2BC3	AuthorityHGNC:4751	Mapping file id3018 NCBI file	EvidenceTAS
GeneH2BC4	AuthorityHGNC:4757	Mapping file id8347 NCBI file	EvidenceTAS
GeneH2BC5	AuthorityHGNC:4747	Mapping file id3017 NCBI file	EvidenceTAS
GeneH2BC6	AuthorityHGNC:4753	Mapping file id8344 NCBI file	EvidenceTAS
GeneH2BC7	AuthorityHGNC:4752	Mapping file id8343 NCBI file	EvidenceTAS
GeneH2BC8	AuthorityHGNC:4746	Mapping file id8339 NCBI file	EvidenceTAS
GeneH2BC9	AuthorityHGNC:4755	Mapping file id8345 NCBI file	EvidenceTAS
GeneH3-3A	AuthorityHGNC:4764	Mapping file id3020 NCBI file	EvidenceTAS
GeneH3-3B	AuthorityHGNC:4765	Mapping file id3021 NCBI file	EvidenceTAS
GeneH3C1	AuthorityHGNC:4766	Mapping file id8350 NCBI file	EvidenceTAS
GeneH3C10	AuthorityHGNC:4775	Mapping file id8357 NCBI file	EvidenceTAS
GeneH3C11	AuthorityHGNC:4771	Mapping file id8354 NCBI file	EvidenceTAS
GeneH3C12	AuthorityHGNC:4774	Mapping file id8356 NCBI file	EvidenceTAS
GeneH3C13	AuthorityHGNC:25311	Mapping file id653604 NCBI file	EvidenceTAS
GeneH3C14	AuthorityHGNC:20503	Mapping file id126961 NCBI file	EvidenceTAS
GeneH3C15	AuthorityHGNC:20505	Mapping file id333932 NCBI file	EvidenceTAS
GeneH3C2	AuthorityHGNC:4776	Mapping file id8358 NCBI file	EvidenceTAS
GeneH3C3	AuthorityHGNC:4768	Mapping file id8352 NCBI file	EvidenceTAS
GeneH3C4	AuthorityHGNC:4767	Mapping file id8351 NCBI file	EvidenceTAS
GeneH3C6	AuthorityHGNC:4769	Mapping file id8353 NCBI file	EvidenceTAS
GeneH3C7	AuthorityHGNC:4773	Mapping file id8968 NCBI file	EvidenceTAS
GeneH3C8	AuthorityHGNC:4772	Mapping file id8355 NCBI file	EvidenceTAS
GeneH4C1	AuthorityHGNC:4781	Mapping file id8359 NCBI file	EvidenceTAS
GeneH4C11	AuthorityHGNC:4785	Mapping file id8363 NCBI file	EvidenceTAS
GeneH4C12	AuthorityHGNC:4784	Mapping file id8362 NCBI file	EvidenceTAS
GeneH4C13	AuthorityHGNC:4791	Mapping file id8368 NCBI file	EvidenceTAS
GeneH4C14	AuthorityHGNC:4794	Mapping file id8370 NCBI file	EvidenceTAS
GeneH4C15	AuthorityHGNC:29607	Mapping file id554313 NCBI file	EvidenceTAS
GeneH4C16	AuthorityHGNC:20510	Mapping file id121504 NCBI file	EvidenceTAS
GeneH4C2	AuthorityHGNC:4789	Mapping file id8366 NCBI file	EvidenceTAS
GeneH4C3	AuthorityHGNC:4787	Mapping file id8364 NCBI file	EvidenceTAS
GeneH4C4	AuthorityHGNC:4782	Mapping file id8360 NCBI file	EvidenceTAS
GeneH4C5	AuthorityHGNC:4790	Mapping file id8367 NCBI file	EvidenceTAS
GeneH4C6	AuthorityHGNC:4783	Mapping file id8361 NCBI file	EvidenceTAS
GeneH4C8	AuthorityHGNC:4788	Mapping file id8365 NCBI file	EvidenceTAS
GeneH4C9	AuthorityHGNC:4793	Mapping file id8294 NCBI file	EvidenceTAS
GeneIFNB1	AuthorityHGNC:5434	Mapping file id3456 NCBI file	EvidenceTAS
GeneJUN	AuthorityHGNC:6204	Mapping file id3725 NCBI file	EvidenceTAS
GeneKDM6B	AuthorityHGNC:29012	Mapping file id23135 NCBI file	EvidenceTAS
GeneMAP2K3	AuthorityHGNC:6843	Mapping file id5606 NCBI file	EvidenceTAS
GeneMAP2K4	AuthorityHGNC:6844	Mapping file id6416 NCBI file	EvidenceIEA, TAS
GeneMAP2K6	AuthorityHGNC:6846	Mapping file id5608 NCBI file	EvidenceTAS
GeneMAP2K7	AuthorityHGNC:6847	Mapping file id5609 NCBI file	EvidenceTAS
GeneMAP3K5	AuthorityHGNC:6857	Mapping file id4217 NCBI file	EvidenceIEA, TAS
GeneMAP4K4	AuthorityHGNC:6866	Mapping file id9448 NCBI file	EvidenceTAS
GeneMAPK1	AuthorityHGNC:6871	Mapping file id5594 NCBI file	EvidenceTAS
GeneMAPK10	AuthorityHGNC:6872	Mapping file id5602 NCBI file	EvidenceTAS
GeneMAPK11	AuthorityHGNC:6873	Mapping file id5600 NCBI file	EvidenceTAS
GeneMAPK14	AuthorityHGNC:6876	Mapping file id1432 NCBI file	EvidenceTAS
GeneMAPK3	AuthorityHGNC:6877	Mapping file id5595 NCBI file	EvidenceTAS
GeneMAPK8	AuthorityHGNC:6881	Mapping file id5599 NCBI file	EvidenceTAS
GeneMAPK9	AuthorityHGNC:6886	Mapping file id5601 NCBI file	EvidenceTAS
GeneMAPKAPK2	AuthorityHGNC:6887	Mapping file id9261 NCBI file	EvidenceTAS
GeneMAPKAPK3	AuthorityHGNC:6888	Mapping file id7867 NCBI file	EvidenceTAS
GeneMAPKAPK5	AuthorityHGNC:6889	Mapping file id8550 NCBI file	EvidenceTAS
GeneMDM2	AuthorityHGNC:6973	Mapping file id4193 NCBI file	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.