{"entity":{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","aka":[],"tldr":"The p53 and RB checkpoints are the cell's brakes. p53 senses damage and stops the cell from copying itself; RB holds the cell at the G1 gate until CDK4/6 unlocks it. Cancers cut these brakes.","summary":"DNA damage activates ATM/ATR → CHK2/CHK1 → p53 stabilisation (MDM2 degrades p53 normally). p53 induces p21, which inhibits CDK4/6-cyclin D and CDK2-cyclin E, keeping RB bound to E2F and the cell in G1. Cyclin D1 amplification, CDK4 amplification, CDKN2A (p16) loss, RB loss, and TP53 mutation (50% of cancers) each release the brake. CDK4/6 inhibitors re-impose it in RB-intact HR+ breast cancer; WEE1 and PLK1 inhibitors exploit G2/M dependence in TP53-mutant cells; MDM2 inhibitors reactivate wild-type p53.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Cell_cycle_checkpoint","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cell_cycle_checkpoint"}],"tags":[],"related":[],"cancers":["breast-hr-positive","tnbc","ovarian","sarcoma","gallbladder"],"sections":[],"technologies":[],"targets":["tp53","cdk4-6","wee1","atr"],"drugs":["palbociclib","ribociclib","abemaciclib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"A checkpoint at a border: p53 is the inspector who halts traffic when something looks wrong, MDM2 is the manager who keeps sending the inspector home, RB is the barrier arm, and CDK4/6 is the motor that lifts it. Cancers bribe the inspector (TP53 mutation) or hot-wire the motor (cyclin D amplification).","nodes":[{"id":"dmg","label":"DNA damage","x":20,"y":5},{"id":"atm","label":"ATM / ATR","x":20,"y":20,"targetId":"atr"},{"id":"p53","label":"p53","x":20,"y":40,"targetId":"tp53"},{"id":"mdm2","label":"MDM2","x":50,"y":30},{"id":"p21","label":"p21","x":20,"y":58},{"id":"cdk46","label":"CDK4/6-cyclin D","x":65,"y":58,"targetId":"cdk4-6"},{"id":"rb","label":"RB","x":65,"y":75},{"id":"e2f","label":"E2F","x":65,"y":90},{"id":"s","label":"S phase (DNA replication)","x":90,"y":97},{"id":"wee1","label":"WEE1 (G2/M)","x":90,"y":40,"targetId":"wee1"}],"edges":[{"from":"dmg","to":"atm","type":"activates"},{"from":"atm","to":"p53","type":"activates"},{"from":"mdm2","to":"p53","type":"inhibits"},{"from":"p53","to":"p21","type":"activates"},{"from":"p21","to":"cdk46","type":"inhibits"},{"from":"cdk46","to":"rb","type":"inhibits"},{"from":"rb","to":"e2f","type":"inhibits"},{"from":"e2f","to":"s","type":"activates"},{"from":"atm","to":"wee1","type":"activates"}],"interventions":["CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib)","WEE1 inhibitors (azenosertib) and PLK1 inhibitors in TP53-mutant tumours","MDM2 inhibitors (brigimadlin) in TP53-wild-type tumours","p53 Y220C reactivator rezatapopt","CDK2 inhibitors for CCNE1-amplified and CDK4/6-resistant disease"]},"route":"/pathways/p53-cell-cycle/","neighbours":{"cancer":[{"id":"adrenocortical","kind":"cancer","name":"Adrenocortical carcinoma","route":"/cancers/adrenocortical/"},{"id":"ampullary","kind":"cancer","name":"Ampullary cancer 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cancer","route":"/cancers/prostate/"},{"id":"retinoblastoma","kind":"cancer","name":"Retinoblastoma","route":"/cancers/retinoblastoma/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"},{"id":"wilms-tumor","kind":"cancer","name":"Wilms tumour (nephroblastoma)","route":"/cancers/wilms-tumor/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"cdkn1a","kind":"target","name":"CDKN1A","route":"/targets/cdkn1a/"},{"id":"e2f7","kind":"target","name":"E2F7","route":"/targets/e2f7/"},{"id":"mdm2","kind":"target","name":"MDM2","route":"/targets/mdm2/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"wee1","kind":"target","name":"WEE1","route":"/targets/wee1/"}],"drug":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"dalpiciclib","kind":"drug","name":"Dalpiciclib","route":"/drugs/dalpiciclib/"},{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","route":"/drugs/eprenetapopt/"},{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"}],"paper":[{"id":"paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018","kind":"paper","name":"Association 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it)","route":"/biomarkers/nepc-transformation/"}],"company":[{"id":"bulsara-bioworks","kind":"company","name":"Bulsara Bioworks","route":"/companies/bulsara-bioworks/"},{"id":"circle-pharma","kind":"company","name":"Circle Pharma","route":"/companies/circle-pharma/"}],"pairing":[{"id":"cdk46-plus-endocrine","kind":"pairing","name":"CDK4/6 inhibitor + endocrine therapy","route":"/pairings/cdk46-plus-endocrine/"}],"person":[{"id":"bruce-stillman","kind":"person","name":"Bruce W. 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