Unravelling mechanisms of p53-mediated tumour suppression - PubMed (original) (raw)

Figure 3. p53 suppresses cancer through transcriptional activation, by regulating diverse biological processes through transactivation of target genes

a ∣ The p53 protein contains two amino-terminal transcriptional activation domains (TADs), a proline-rich domain (PRD), a DNA-binding domain (DBD), a tetramerization domain (TET) and a carboxy-terminal region that is rich in basic residues (Basic). Inactivation of p53 in human tumours typically occurs through missense mutations in the DBD of the p53 protein. Six common p53 ‘hot-spot’ mutations are categorized as either structural or contact p53 mutants, both of which disrupt the protein–DNA interaction and the transactivation of p53 target genes (see also BOX 1). b ∣ Lists of key p53-induced target genes involved in processes that are important for tumour suppression, including the canonical p53-associated responses — apoptosis, cell cycle arrest, senescence and DNA repair (purple) — as well as processes that have recently been associated with p53-dependent tumour suppression, such as metabolism control, autophagy, tumour microenvironment crosstalk, invasion and metastasis, and stem cell biology,,,,– (beige). The evidence for p53-dependent regulation of the genes on this list comes from mouse and/or human cells. Most of the genes are regulated by p53 in both human and mouse cells, but a few of the genes have currently only been identified and/or shown to be regulated by p53 in one of these species. Adora2b, adenosine A2b receptor; Aldh4, aldehyde dehydrogenase 9 family, member A1; Apaf1, apoptotic peptidase activating factor 1; Atg, autophagy related; Bai1, brain-specific angiogenesis inhibitor 1; Bax, BCL-2-associated X protein; Btg2, B cell translocation gene 2, anti-proliferative; Cdkn1a, cyclin-dependent kinase inhibitor 1A; Ctsd, cathepsin D; Cx3cl1, chemokine (C-X3-C motif) ligand 1; Ddb2, damage-specific DNA binding protein 2; Ddit4, DNA-damage-inducible transcript 4; Dram1, DNA-damage regulated autophagy modulator 1; Ercc5, excision repair cross-complementing rodent repair deficiency, complementation group 5; Fancc, Fanconi anaemia, complementation group C; Foxo3, forkhead box O3; Gadd45a, growth arrest and DNA-damage-inducible 45α; Gamt, guanidinoacetate _N_-methyltransferase; Gls2, glutaminase 2; Gpx1, glutathione peroxidase 1; Icam1, intercellular adhesion molecule 1; Irf, interferon regulatory factor; Laptm4a, lysosomal protein transmembrane 4α; Lkb1, liver kinase B1 (also known as Stk11); Lpin1, lipin 1; Mcp1, monocyte chemoattractant protein 1 (also known as Ccl2); Mgmt, _O_-6-methylguanine-DNA methyltransferase; Ncf2, neutrophil cytosolic factor 2; Pai1, plasminogen activator inhibitor; Perp, p53 apoptosis effector; Pig3, p53 inducible protein 3 (also known as Tp53i3); Pidd, p53-induced death domain protein; Pik3r3, phosphoinositide-3-kinase, regulatory subunit 3; Pml, promyelocytic leukaemia; pol, polymerase; Polk, DNA polymerase-κ; Prka, protein kinase, AMP-activated; Prkag2, protein kinase, AMP-activated, γ2 non-catalytic subunit; Ptprv, protein tyrosine phosphatase, receptor type, V; Sesn, sestrin; Tigar, TP53-induced glycolysis and apoptosis regulator; Tlr, Toll-like receptor; TP53AIP1, tumour protein p53 regulated apoptosis inducing protein 1; Tp53inp1, tumour protein p53 inducible nuclear protein 1; Tpp1, tripeptidyl peptidase I; Tsc2, tuberous sclerosis 2; Tsp1, thrombospondin 1; Ulbp, UL16 binding protein; Ulk, UNC-51 like autophagy activating kinase; Uvrag, UV radiation resistance associated; Vamp4, vesicle-associated membrane protein 4; Vmp1, vacuole membrane protein 1; Xpc, xeroderma pigmentosum, complementation group C.