br Discussion and conclusion Ubiquitination

Discussion and conclusion Ubiquitination and deubiquitination have emerged as important mechanisms involved in p53 management. This review revealed that various DUBs can regulate p53 or p53-Mdm2-MdmX networks. Herein, we reviewed the current progress made toward elucidating the complexities in the regulation of the p53 tumor suppressor pathway by DUBs and the biological functions of those DUBs including their capacity to positively and negatively regulate p53. Furthermore, the review organized DUBs according to their capacity to directly or indirectly regulate p53 (Table 1). Regulation of p53 stability during cellular stress conditions is an important topic in cancer research, and it would be interesting, in future studies, to examine whether different DUBs may cooperate with each other to synergistically regulate p53 stability and activity. This review provides clues to how these multiple DUBs may coordinate to ensure tight, precise, and dynamic control of stability and activity of p53. The half-life of p53 is short, and its expression is limited by E3 ubiquitin ligases-mediated pathways under normal cell conditions [48], [89]. When O-1602 are damaged, p53 is expressed at a high level, and that expression level must be maintained until the damage has been overcome [89]. In addition, p53 is active in tumor suppression and promotes cell apoptosis [89], and it is present as a mutated or impaired form in more than half of human diseases [90], [91]. Additionally, in approximately 80% of human tumors, p53 is inactive or being expressed at a low level [91]. Under some cellular stress conditions, presence of mutated and/or inactivated p53 can result in cell malfunction [92]. Furthermore, such conditions can trigger diseases that produce malignancy or tumor [92]. Hence, regulation of p53 stability during cellular stress conditions is an important research field for cancer treatment. The p53 can undergo various PTM processes including ubiquitination, acetylation, SUMOylation, and neddylation [93]. Among the PTM processes, this review highlighted p53 ubiquitination and focused on p53-associated-DUBs. The UPP is a basic cellular process involved in human pathogenesis including cancer, autoimmune diseases, and inflammatory responses, and p53 is directed by the UPP via several E3 ligases [81]. Ubiquitinated p53, when degraded, regulates numerous functions as a tumor suppressor. Various p53-associated DUBs counteract and interrupt p53 ubiquitination. These DUBs affect p53 in several ways by targeting p53 upregulation and down-regulation directly or indirectly (Table 1). Therefore, some of the DUBs that regulate p53 stability are potential candidates for application in cancer treatment. Targeting DUBs associated with p53 can contribute to controlling p53 expression and/or p53 function in human diseases, especially cancers. Furthermore, DUBs may also be suppressed and/or activated and function as p53 inhibitors. For example, WP1130 targets and represses USP5 and USP9X in p53-related ubiquitination and deubiquitination processes [72]. In addition, USP7 is suppressed by various DUB inhibitors including HBX41108 and P22077, thereby regulating p53 [94], [95], [96]. Inversely, our recent study affirmed that USP5 and OTUD6A are regulated by the presence of p53 (data not shown). During this study, we noted that USP5 was overexpressed in p53-null cells, whereas USP5 expression was lowered in p53-expressing cells (data not shown). In addition, USP5 is able to modulate p53 ubiquitination, subsequently hindering the effects of p53-related pathways [83]. Thus, the interaction between USP5 and p53 can result in negative regulation. This review describes the currently reported variety of DUBs within the ubiquitination and deubiquitination pathways of p53 and, in particular, the important interactions between those DUBs and p53. These interactions have significant implications in the future development of targeted therapies for application in p53-related cancers. Through this review, we hope to provide insight into various potential candidates for p53-related cancer therapeutics.