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. 2022 Oct 7;54(10):1658–1669. doi: 10.1038/s12276-022-00863-4

Fig. 2. Simplified schematic showing the activation and deactivation of the p53 network in response to a DNA-damaging agent.

Fig. 2

Under stress conditions, such as ionizing radiation (IR), p53 is rapidly stabilized primarily through phosphorylation mediated by different upstream regulators, such as ATM and ATR. Phosphorylated p53 is stabilized mainly through its disassociation from HDM2 and UBE4B; hence, p53 protein accumulates and is translocated into the nucleus. In the nucleus, p53 aggregates as tetramers, the active forms of p53, and transcriptionally activates or suppresses its targeted genes, including cyclin-dependent kinase inhibitor p21 and proapoptotic genes Puma and Bax. Moreover, phosphorylated p53 transcriptionally induces most of its negative regulators, including HDM2, UBE4B, and Wip1, via negative feedback loops. Once DNA damage is resolved or p53 activity is not needed, p53 and most of its negative and positive regulators undergo dephosphorylation by Wip1. Moreover, UBE4B binds and degrades phosphorylated p53. This figure was created using BioRender.com (granted a license “Academic License Terms”, No. BH246NTRVL).