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  • br Regulation of p via the ubiquitin proteasome


    Regulation of p53 via the ubiquitin-proteasome pathway Studies into regulation of p53 via PTM processes that involve phosphorylation, acetylation, ubiquitination, SUMOylation, neddylation, and methylation are being increasingly reported [23], [24]. Phosphorylation and acetylation of p53 stimulate p53-associated transcription factors [25], [26], whereas ubiquitination, SUMOylation, and neddylation of p53 repress p53-related transcription factors and affect the nuclear export of p53 [25], [26]. Lastly, methylation of p53 at K382 inhibits p53 binding to the promoters of p21 and PUMA in a manner that affects both activation and inactivation of p53 plk1 inhibitor [25], [26]. Among several previous studies, one report suggests that the ubiquitination level of p53 is elevated via treatment with the proteasome inhibitor, MG132 [27]. The results in that study demonstrated that p53 is degraded through the 26S proteasome, and that p53 stability is controlled by ubiquitin-dependent degradation. Interestingly, p53 depends on attached ubiquitins such as monoubiquitins or polyubiquitins [26]. Formed monoubiquitins or K63 polyubiquitins on p53 are involved in p53 nuclear export and cytosolic localization, whereas K48 polyubiquitins on p53 reduces p53 stability via protein degradation [26]. Modulation of p53 by ubiquitin affects both p53 expression and activation [24]. While p53 is ubiquitinated, various E3 ligases enable ubiquitin to tag p53, and ubiquitin-tagged p53 negatively regulates stability via the UPP (Fig. 3). Mouse double minute 2 homolog (Mdm2) is identified as an E3 ligase of p53, and it accelerates p53 degradation [28], [29]. Mdm2 has a RING domain and the capability of self-control via auto-ubiquitination [26]. Until p53 is activated in response to cell stress, Mdm2 maintains p53 at a sufficiently low level for homeostasis by continuously disassembling p53 [30]. Thus, regulation of Mdm2 level is an important determinant of p53 function. Mdm2 shares comparable sequences in the RING domain with the murine double minute 4 (MdmX) homolog [31]. Interaction between Mdm2 and MdmX via their RING domains facilitates ubiquitination of p53 [32], [33]. Even though MdmX does not provide E3 activity to p53, its RING domain can control p53 stability [31]. In this way, both Mdm2 and MdmX are negative controllers of p53 expression. Ubiquitin-protein ligase E3A (UBE3A), otherwise called ubiquitin-protein ligase (E6AP), activates ubiquitin-dependent degradation of p53 by influencing Mdm2 [34], [35]. Furthermore, ARF-BP1, as an Mdm2-independent E3, regulates p53 stability and activity [36]. In addition, constitutive photomorphogenic 1 (COP1) modulates ubiquitin-dependent degradation of p53 as an Mdm2-independent E3 ligase [37]. Moreover, Pirh2 interacts with and ubiquitinates p53 independently of Mdm2; therefore, Pirh2 is a negative regulator of p53 [38]. In particular, the caspase 8/10-associated RING domain protein (CARP) targets phospho-p53 expression for degradation [39]. In addition, there are other diverse E3 ligases for p53 known as male-specific lethal 2 (MSL2), parkin-like ubiquitin ligase (Parc), TNFR-associated factor (TRAF7), and Cullin 4B [40], [41], [42], [43]. Those E3 ligases catalyze the interaction between ubiquitin and p53 and, subsequently, activate ubiquitin-dependent degradation of p53 [44]. Therefore, they have also been identified as negative-feedback regulators due to their ability to downregulate p53 stability [44]. Negative regulation of p53 stability can affect various diseases, including cancers [45]. Thus, modulation of ubiquitinated p53 is an important topic for anti-cancer research, and there will surely be further research into p53 modulation.
    Positive regulation of ubiquitinated p53
    Negative regulation of ubiquitinated p53
    Regulation of acetylated p53 by DUBs It has been reported that several DUBs target acetylated p53 as well as ubiquitinated p53. USP4 targets ubiquitinated p53 by deubiquitinating ARF-BP1 and targets acetylated p53 by stabilizing HDAC [79], [80]. Previous study has also demonstrated that USP4 inhibits p53 functions by deubiquitinating HDAC [80]. In addition, USP22 has a role in suppression of acetylation and transcriptional actions of p53 by balancing the action of Sirt1 [87]. USP22 attaches to and deubiquitinates Sirt1, which contributes to deactivation of p53 and regulation of p53-related apoptosis during embryonic development and under DNA damage conditions [87]. Based on the presence of a Sirt1 adjustment by USP22, a previous study indicated that USP22 is a fundamental cell cycle controller that can downregulate p53 and actuate cell expansion in HeLa cells [88].