Loading
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.
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).
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).
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
This review fixed the picture of p53 as the guardian of the genome that every textbook uses. It explains why TP53-mutant cancers are aggressive and hard to treat, why MDM2 inhibitors are being developed to reactivate wild-type p53, and why germline TP53 testing matters in families.
Shares Hallmark: evading growth suppressors, CDKN1A, WEE1, DNA replication stress and the tags mechanism, mechanics-atlas.
Shares WEE1, ATR, DNA replication stress, Synthetic lethality: paired dependencies and the tags mechanism, mechanics-atlas.
Shares Synthetic lethality approaches, Germline vs somatic mutations, p53 / RB / cell-cycle checkpoint, Germline (hereditary) testing and the tags mechanism, mechanics-atlas.
Shares ATR, DNA replication stress, MYC and the tags mechanism, mechanics-atlas.
Shares Intrinsic apoptosis (BCL-2 family), BCL-2, Venetoclax and the tags mechanism, mechanics-atlas.
Shares Intrinsic apoptosis (BCL-2 family), BCL-2, p53 / RB / cell-cycle checkpoint, TP53 and the tags mechanism, mechanics-atlas.
Shares ATR, DNA replication stress, Ovarian cancer and the tags mechanism, mechanics-atlas.
Shares Cellular senescence, BCL-2, Venetoclax and the tags mechanism, mechanics-atlas.