Category: signaling
p53 (TP53) is the "guardian of the genome" — a transcription factor that senses cellular stress (DNA damage, oncogene activation, hypoxia, nutrient deprivation, ribosomal stress) and triggers cell-cycle arrest, senescence, or apoptosis. Mutated in ~50% of human cancers (most frequently mutated tumor suppressor). Steady-state regulation: MDM2 (HDM2 in humans) is an E3 ubiquitin ligase that polyubiquitinates p53 → proteasomal degradation. p53 transcribes MDM2 → negative-feedback loop; basal p53 levels stay low. Stress-induced stabilization: (1) DNA damage — ATM/ATR sense DSBs + replication stress → phosphorylate p53 (Ser15, Ser20) + MDM2 → disrupts MDM2-p53 binding. (2) Oncogene activation — ARF (p14ARF) binds + sequesters MDM2 → p53 stabilizes. (3) Ribosomal stress — RPL5/RPL11 bind MDM2. Stabilized p53 → tetramerizes + binds p53RE → transcribes p21 (cell-cycle arrest), PUMA + BAX + NOXA (apoptosis), GADD45, MDM2 (feedback), p53R2 (DNA repair). Decision logic: low / transient stress → p21 → reversible arrest. Moderate persistent stress → senescence (cross-link [[senescence_sasp_senolytics]]). High / unrepairable → BAX/PUMA → apoptosis (cross-link [[apoptosis_bcl2_axis]]). Hotspot mutations (R175H, R248Q/W, R273H/C, R282W) — loss of DNA binding + gain-of-function. Li-Fraumeni: germline TP53 → early-onset cancers. Therapeutic landscape: MDM2-p53 interaction inhibitors (idasanutlin, milademetan, navtemadlin — reactivate WT p53; toxicity is challenging); reactivators of mutant p53 (APR-246 in MDS); many natural products (curcumin, resveratrol, quercetin, withaferin-A) restore p53 function in preclinical cancer models. Cross-links: [[apoptosis_bcl2_axis]], [[senescence_sasp_senolytics]], [[cell_cycle_cdk]], [[ubiquitin_proteasome]] (MDM2-mediated p53 turnover).