Essential Roles of E3 Ubiquitin Ligases in p53 Regulation.

Sanam Sane,Khosrow Rezvani

doi:10.3390/ijms18020442

Sanam Sane, Khosrow Rezvani

Open Access

https://doi.org/10.3390/ijms18020442

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Abstract

The ubiquitination pathway and proteasomal degradation machinery dominantly regulate p53 tumor suppressor protein stability, localization, and functions in both normal and cancerous cells. Selective E3 ubiquitin ligases dominantly regulate protein levels and activities of p53 in a large range of physiological conditions and in response to cellular changes induced by exogenous and endogenous stresses. The regulation of p53’s functions by E3 ubiquitin ligases is a complex process that can lead to positive or negative regulation of p53 protein in a context- and cell type-dependent manner. Accessory proteins bind and modulate E3 ubiquitin ligases, adding yet another layer of regulatory control for p53 and its downstream functions. This review provides a comprehensive understanding of p53 regulation by selective E3 ubiquitin ligases and their potential to be considered as a new class of biomarkers and therapeutic targets in diverse types of cancers.

Highlights

In mammalian cells, p53 protein is at the hub of a plethora of regulatory and signaling pathways that are crucial for cell-fate control
With 393 amino acids, p53 protein contains a complex set of domains. p53 has a transactivation domain (TAD) located at the N-terminus of protein that is further subdivided into two homologous subdomains, TAD1 and TAD2, followed by a proline-rich region [1]
This review focuses on four E3 ubiquitin ligases that selectively and dominantly target p53 in tumors

Summary

Introduction

P53 protein is at the hub of a plethora of regulatory and signaling pathways that are crucial for cell-fate control. By binding to Mdm, the ribosomal protein L11 (RPL11) blocks Mdm2-mediated p53 ubiquitination and degradation, resulting in activation of p53’s downstream tumor suppressor activities, including cell cycle arrest [75]. Mdm and its interaction with diverse protein partners (illustrated in Figure 1) indicate that the activity of Mdm occurs under a complex regulatory network that modulates the ubiquitination and proteasomal degradation of p53 in a cell-context-dependent manner. A recent study completed by Yang et al reported that a microRNA named miR-100 can enhance ubiquitination and proteasomal degradation of p53 protein in poorly differentiated gastric cancer cells while non-cancerous gastric cells remain intact Their results indicate that knocking down miR-100 reduces the expression of Pirh, a key E3 ubiquitin ligase for p53 ubiquitination in gastric cancer cells, resulting in stabilization and upregulation of p53 in gastric cancer cells and activation of p53’s downstream apoptosis pathway.

Discussion

Findings

Ubiquitin E3 ULbigiqasueitin