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. 2020 Apr 16;11:327. doi: 10.3389/fphys.2020.00327

FIGURE 2.

FIGURE 2

Comprehensive diagram representing the existing bidirectional interaction within the PER2:p53:MDM2 network. Cartoon representation depicting the four major regulatory nodes in p53, PER2, and MDM2 signaling. Node 1: PER2 modulates p53 stability by preventing MDM2-mediated ubiquitylation and proteasomal degradation of p53. Node 2: PER2:p53 binding favors p53 shuttling to the nucleus where it binds MDM2 and forms a stable trimeric complex. Node 3: Dissociation of PER2:p53 facilitates each component’s transcriptional activity and expression of downstream target genes. Node 4: Accumulation of PER2:MDM2 in the nucleus results in PER2 polyubiquitylation and degradation in a process that influences circadian period length. de-Ub, de-ubiquitylase; ub, ubiquitin; CK1δ/ε, casein kinase 1 δ/ε; CRY, cryptochrome; β-TrCP, β-transducin repeat-containing protein; PER2, period 2; MDM2, mouse double minute-2 homolog protein; C/B, circadian locomotor output cycles kaput/BMAL1 (Brain and Muscle ARNT-like (CLOCK/BMAL1); E-box, Enhancer element; g-IR, irradiation. Delay: represents the phase delay that results from PER2-mediated p53 shuttling.