{"entity":{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","aka":[],"tldr":"p53 is the cell's emergency coordinator: DNA damage, oncogene stress or lack of oxygen switch it on, and it then pauses division, orders repairs, or triggers suicide or permanent retirement, while MDM2 keeps it off in healthy cells. About half of cancers mutate p53 outright, and sarcomas, gliomas, melanomas and retinoblastomas silence it instead by amplifying MDM2 or MDM4.","summary":"Stress inputs converge on p53 stabilisation: DNA damage via ATM/ATR-CHK2/CHK1 phosphorylation, oncogene activation via p14ARF (CDKN2A) sequestering MDM2, ribosomal stress via RPL5/RPL11, hypoxia. MDM2 (with MDMX/MDM4) ubiquitinates p53 for proteasomal degradation and is itself a p53 target, forming a negative feedback loop. Active p53 tetramers transactivate CDKN1A (p21, arrest), PUMA/NOXA/BAX (apoptosis), GADD45/DDB2 (repair), TIGAR/SCO2 (metabolism), and senescence programmes; outcome depends on stress intensity and cofactors. TP53 mutations (~50% of cancers) are mostly missense DNA-binding-domain hotspots (R175, R248, R273) with dominant-negative and gain-of-function effects; MDM2 amplification (sarcoma, glioma) and MDM4 amplification (melanoma, retinoblastoma) silence wild-type p53. Drugs: MDM2 inhibitors (milademetan, brigimadlin, navtemadlin) in TP53-wild-type disease, limited by thrombocytopenia; Y220C reactivator rezatapopt; eprenetapopt (APR-246) failed in MDS; TP53 status guides WEE1/ATR synthetic lethality and predicts chemoresistance in CLL (del17p).","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/P53","links":[{"label":"Kastenhuber & Lowe, Putting p53 in context (Cell 2017)","url":"https://doi.org/10.1016/j.cell.2017.08.028"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["sarcoma","cll","mds","ovarian","gallbladder"],"sections":[],"technologies":["germline-testing","cgp","synthetic-lethality-approaches"],"targets":["tp53","mdm2","atr","wee1","bcl2"],"drugs":["eprenetapopt","venetoclax"],"companies":[],"institutions":[],"pathways":["p53-cell-cycle","apoptosis-bcl2","senescence","replication-stress"],"terms":["li-fraumeni","del17p-tp53","evading-growth-suppressors","germline-vs-somatic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kastenhuber-cell"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A fire marshal who is normally kept locked in a cupboard (by MDM2). When alarms sound, the cupboard opens and the marshal stops work, calls repairs, and if the building is beyond saving, orders evacuation (apoptosis) or condemns it (senescence). Cancers either sack the marshal (TP53 mutation) or weld the cupboard shut (MDM2 amplification).","nodes":[{"id":"dmg","label":"DNA damage (ATM/ATR)","x":12,"y":12,"targetId":"atr"},{"id":"onc","label":"Oncogene stress → ARF","x":40,"y":12},{"id":"hyp","label":"Hypoxia, ribosome stress","x":70,"y":12},{"id":"mdm2","label":"MDM2 / MDMX","x":82,"y":42,"targetId":"mdm2"},{"id":"p53","label":"p53","x":45,"y":45,"targetId":"tp53"},{"id":"mut","label":"TP53 mutation (~50%)","x":12,"y":45},{"id":"arr","label":"p21 → arrest","x":12,"y":82},{"id":"apo","label":"PUMA, NOXA → apoptosis","x":40,"y":82,"targetId":"bcl2"},{"id":"sen","label":"Senescence, repair","x":70,"y":82}],"edges":[{"from":"dmg","to":"p53","type":"activates"},{"from":"onc","to":"mdm2","type":"inhibits"},{"from":"hyp","to":"p53","type":"activates"},{"from":"mdm2","to":"p53","type":"inhibits"},{"from":"p53","to":"mdm2","type":"activates"},{"from":"mut","to":"p53","type":"inhibits"},{"from":"p53","to":"arr","type":"activates"},{"from":"p53","to":"apo","type":"activates"},{"from":"p53","to":"sen","type":"activates"}],"interventions":["MDM2 inhibitors (brigimadlin, milademetan, navtemadlin) for TP53-wild-type, MDM2-amplified tumours","Mutant p53 reactivators: rezatapopt (Y220C); eprenetapopt failed in phase 3 MDS","TP53-mutant tumours are approached via WEE1, ATR, PLK1 dependence and via p53-independent chemotherapy","TP53 status as biomarker: del17p CLL, MDS/AML risk, Li-Fraumeni surveillance"]},"route":"/pathways/p53-mdm2-axis/","neighbours":{"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","route":"/cancers/mds/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"richter-transformation-cll","kind":"cancer","name":"Richter transformation of chronic lymphocytic leukaemia","route":"/cancers/richter-transformation-cll/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"cdkn1a","kind":"target","name":"CDKN1A","route":"/targets/cdkn1a/"},{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"mdm2","kind":"target","name":"MDM2","route":"/targets/mdm2/"},{"id":"mdm4","kind":"target","name":"MDM4","route":"/targets/mdm4/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"wee1","kind":"target","name":"WEE1","route":"/targets/wee1/"}],"drug":[{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","route":"/drugs/eprenetapopt/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"pathway":[{"id":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"oncogenic-viruses","kind":"pathway","name":"Oncogenic viruses","route":"/pathways/oncogenic-viruses/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"},{"id":"ubiquitin-proteasome-system","kind":"pathway","name":"Ubiquitin-proteasome system & protein homeostasis","route":"/pathways/ubiquitin-proteasome-system/"}],"term":[{"id":"del17p-tp53","kind":"term","name":"del(17p) / TP53 aberration in CLL","route":"/terms/del17p-tp53/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"evading-growth-suppressors","kind":"term","name":"Hallmark: evading growth suppressors","route":"/terms/evading-growth-suppressors/"},{"id":"li-fraumeni","kind":"term","name":"Li-Fraumeni syndrome (germline TP53)","route":"/terms/li-fraumeni/"},{"id":"lymphoma-bio-transformation","kind":"term","name":"Transformation: when a slow lymphoma turns into a fast one","route":"/terms/lymphoma-bio-transformation/"}],"paper":[{"id":"paper-levine-p53-gatekeeper-cell-1997","kind":"paper","name":"Levine 1997: p53, the cellular gatekeeper for growth and division","route":"/key-papers/paper-levine-p53-gatekeeper-cell-1997/"},{"id":"paper-kastenhuber-cell","kind":"paper","name":"Putting p53 in Context","route":"/key-papers/paper-kastenhuber-cell/"},{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","route":"/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/"}]}}