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. 2022 Jan 26;10:818744. doi: 10.3389/fcell.2022.818744

FIGURE 1.

FIGURE 1

Schematic summary of important genetic and protein features of p53, MDM2 and ARF. (A) p53 interacts with MDM2 through its transactivation domain (TAD), DNA binding domain (DBD) and carboxy-terminal domain (CTD). MDM2-mediated post-translational modifications occur at the CTD, leading to inactivation and degradation of p53. Single nucleotide polymorphisms (SNP) in TAD (P47S; rs1800371) and proline-rich domain (PRD) (P72R; rs1042522) modulate p53’s ability to suppress tumorigenesis and regulate metabolic fitness. Temperature sensitive mutations of p53 in DBD (A138V and R282W) result in resistance to MDM2-mediated degradation. OD, oligomerization domain. (B) Upper panel: SNPs of MDM2 regulate the functional oscillation between p53 and MDM2. SNP309T>G (rs2279744) results in higher MDM2 expression and inhibits p53-MDM2 oscillation. SNP285G>C (rs117039649) contributes to lower MDM2 expression and is associated with reduced risks for female reproductive cancers. Lower panel: MDM2 interacts with p53 through its N-terminal hydrophobic domain (HD) and acid domain (AD), and with ARF through AD. Interaction with ARF exposes the NoLS motif in the RING domain (RD) to sequester the ARF-MDM2 complex in the nucleolus. A cancer-associated single mutation, C305F, in the zinc finger domain (ZFD) mediates interaction between MDM2 and ribosomal proteins (RP) to regulate p53 function in response to metabolic stress. Two mutations in RD (I440K and Y489A) reduce MDM2-mediated p53 degradation but still limit p53 activity in response to DNA damage. (C) Upper panel: The p16INK4A/p14ARF locus. Each transcript utilizing a unique first exon, p16INK4A (Exon 1α) and p14ARF (Exon 1β) splice into common exon 2 and 3 in alternate reading frames to produce two distinctive amino acid sequences, resulting in two unrelated proteins. Lower panel: ARF interacts with MDM2 and NPM through its conserved N-terminal motif between amino acids 1 and 14. Both 1–14 and 82–101 arginine rich NoLS motifs are important for ARF’s ability to translocate to the nucleolus and activate p53. The figure was created with BioRender.com and not drawn to scale.