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Fig. 2 | Journal of Hematology & Oncology

Fig. 2

From: Targeting mutant p53 for cancer therapy: direct and indirect strategies

Fig. 2

Multiple anticancer therapeutic strategies targeting p53. The p53 protein, encoded by the TP53 gene, consists of five functional regions: TA, PR, DBD, OD, and CTD. (Left) After being imported into the nucleus and tetramerized, wtp53 proteins acquire the ability to bind with their target genes (e.g., p21, Bax, PIGs, PAI) to induce tumor-suppressive responses (cell cycle arrest, apoptosis, and senescence) to suppress tumor initiation or progression. The ubiquitin E3 ligase MDM2 directly binds to p53 proteins and promotes proteasomal degradation. For cancers containing wtp53, MDM2 inhibitors (e.g., AMG232 and RG7388) prevent p53 from proteasomal degradation and promote its tumor-suppressive functions via disrupting the p53-MDM2 protein–protein interaction. (Right) Most mutations of mutp53 proteins occur in the DBD regions, including several hotspot mutation sites (175, 220, 245, 248, 249, 273, 282). Mutp53 proteins lose the ability to bind with tumor-suppressive genes and even acquire functions to transcriptionally activate oncogenic genes (e.g., NF-κB2, TGFβ-R2, BRCA1) to induce tumor-promoting responses such as inflammation and metabolic reprogramming. Mutp53 reactivators target specific p53 mutations (e.g., APR-246 targets p53 R175H and R273H, and COTI-2 targets p53 R175H) to restore wtp53 functions. Additionally, mutp53 inhibitors directly bind to mutp53 (e.g., HDAC inhibitor for p53 R175H, R280K and V247F/P223L, and disulfiram for p53 R273H) to promote degradation. TA: transactivation domain; PR: proline-rich domain; DBD: DNA-binding domain; OD: oligomerization; CTD: carboxyl-terminal domain; Ub: ubiquitin

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