The p53 network (guardian of the genome)
p53 is the cell's emergency coordinator. Damage, oncogene stress, or lack of oxygen switch it on; it then pauses division, orders repairs, or triggers suicide or permanent retirement. MDM2 keeps it switched off in healthy cells. Half of all cancers break p53 outright; many of the rest over-produce MDM2.
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).
In one picture
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).
Diagram
top- 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
Pages like this
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- PathwayDouble-strand break repair: HR versus end joining
Shares WEE1, ATR, DNA replication stress, Synthetic lethality: paired dependencies and the tags mechanism, mechanics-atlas.
- PathwayDrivers, passengers & the two-hit model
Shares Germline vs somatic mutations, Synthetic lethality approaches, p53 / RB / cell-cycle checkpoint, Germline (hereditary) testing and the tags mechanism, mechanics-atlas.
- PathwayExtrinsic apoptosis (death receptors)
Shares Intrinsic apoptosis (BCL-2 family), BCL-2, Venetoclax and the tags mechanism, mechanics-atlas.
- PathwayMismatch repair & microsatellite instability
Shares Synthetic lethality: paired dependencies, Synthetic lethality approaches, Germline (hereditary) testing, Comprehensive genomic profiling and the tags mechanism, mechanics-atlas.
- PathwayMitosis & the spindle assembly checkpoint
Shares Intrinsic apoptosis (BCL-2 family), BCL-2, p53 / RB / cell-cycle checkpoint, TP53 and the tags mechanism, mechanics-atlas.
- PathwayBase excision repair, PARP & alkylation damage
Shares ATR, DNA replication stress, Ovarian cancer and the tags mechanism, mechanics-atlas.
- PathwayDrug-tolerant persister cells
Shares Cellular senescence, BCL-2, Venetoclax and the tags mechanism, mechanics-atlas.