The MDM2-p53 pathway revisited

Abstract

The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.

The Roles of MDM2 and MDMX in Cancer

“…Increasing numbers of RPs have been shown to play a part in regulating the p53–MDM2 pathway upon ribosomal stress (reviewed in 133). Several ribosomal proteins, including RPL5, RPL11, and RPL23, have been shown to interact with the MDM2 central acidic motif in a similar, yet distinct, manner.…”

USP11 regulates p53 stability by deubiquitinating p53

“…p53 is kept at very low levels in normal cells and dramatically stabilized in response to a variety of stress signals, including DNA damage, abnormal oncogenic activation, and hypoxia (Harris and Levine, 2005;Kruse and Gu, 2009;Vousden and Prives, 2009). The stability of p53 is primarily regulated by its negative regulator murine double minute 2 (Mdm2), which binds p53 and functions as an E3 ubiquitin ligase leading to p53 ubiquitination and degradation (Haupt et al, 1997;Honda et al, 1997;Kubbutat et al, 1997;Nag et al, 2013).…”

RASSF10 is Epigenetically Inactivated and Suppresses Cell Proliferation and Induces Cell Apoptosis by Activating the p53 Signalling Pathway in Papillary Thyroid Carcinoma Cancer

“…Epigenetically inactivated RASSF10 has been suggested in diverse tumours, including prostate carcinoma, glioblastoma, skin malignant melanoma and thyroid cancer [11-14]. Previous findings have indicated that RASSF10 might suppress the growth of colorectal and hepatocellular carcinomas, as well as stimulate cell cycle arrest and cell apoptosis by activating p53 signalling [15-18]. The dominant components of p53 signalling, including p53, p21, Bcl-2 and Bax, have been extensively studied in carcinomas [16, 19].…”

“…Among these factors, the p53 mutation appears to be the most frequent genetic alteration observed in tumour cells. For instance, the mutated form of p53 regularly appears in undifferentiated thyroid carcinomas [20-22], and MDM2, another pivotal element of p53 signalling, can directly catalyse p53 degradation by exacerbating p53 ubiquitination [18, 23]. …”