Mdm2-RNA Interactions as a Target for Cancer Therapy: It’s Not All About p53

Bohlman, Stephen; Manfredi, James J.

doi:10.1016/j.ccell.2016.09.017

Cited by 6 publications

(10 citation statements)

References 11 publications

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“…Most patents for MDM2 antagonists concern small molecule inhibitors, e.g., Nutlin-3a and RG7112. Some of these molecules are currently under phases I, II and III of clinical trials (Li and Lozano, 2013;Bohlman and Manfredi, 2016;Burgess et al, 2016). Since cardiovascular side effects of anti-cancer therapies are a recurrent problem (Jain et al, 2017), characterizing the cardiovascular function of MDM2 has become a pressing issue.…”

Section: Introductionmentioning

confidence: 99%

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

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Section: Introductionmentioning

confidence: 99%

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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“…Recent studies have identified E3 ubiquitin ligase MDM2 as a novel therapeutic target in cervical cancer, unveiling a great treatment opportunity for cervical cancer patients [4,[19][20][21][22][23]. MDM2, known as Murine double minute 2, is known to be a negative regulator of p53 tumor suppressor gene [22].…”

Section: Discussionmentioning

confidence: 99%

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

et al. 2020

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Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that mdm2 (Murine double minute 2) gene was amplified and/or overexpressed in a variety of human neoplasms, including cervical cancer. Furthermore, MDM2 is critical to cervical cancer development and progression. Relatively studies have reported that USP15 and USP7 stabilized MDM2 protein levels by removing its ubiquitin chain. In the current study, we studied the cell proliferation status after IU1 treatment and the USP14-MDM2 protein interaction in cervical cancer cells. This study experimentally revealed that IU1 treatment reduced MDM2 protein expression in HeLa cervical cancer cells, along with the activation of autophagy-lysosomal protein degradation and promotion of ubiquitin-proteasome system (UPS) function, thereby blocked G0/G1 to S phase transition, decreased cell growth and triggered cell apoptosis. Thus, these results indicate that IU1 treatment simultaneously targets two major intracellular protein degradation systems, ubiquitin-proteasome and autophagy-lysosome systems, which leads to MDM2 degradation and contributes to the antitumor effect of IU1.

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“…Another strategy is to target MDM2 and its interaction with mRNA that encodes the X-linked inhibitor of apoptosis protein (XIAP) [ 122 ]. Binding of the MDM2 protein to the internal ribosome entry site (IRES) on the mRNA encoding the anti-apoptotic XIAP results in stabilization of MDM2 protein and increased translation of XIAP [ 123 ]. This regulatory mechanism is not dependent on p53 status, and the ability to modulate two independent pathways by disrupting a single interaction could be a benefit of this novel therapeutic approach [ 123 ].…”

Section: Therapeutic Considerations and Conclusionmentioning

confidence: 99%

“…Binding of the MDM2 protein to the internal ribosome entry site (IRES) on the mRNA encoding the anti-apoptotic XIAP results in stabilization of MDM2 protein and increased translation of XIAP [ 123 ]. This regulatory mechanism is not dependent on p53 status, and the ability to modulate two independent pathways by disrupting a single interaction could be a benefit of this novel therapeutic approach [ 123 ]. Using a fluorescence polarization assay for high throughput screening of chemical libraries, Gu et al identified a panel of inhibitors that block protein-RNA interaction (MDM2-XIAP) leading to MDM2 degradation [ 122 ].…”

Section: Therapeutic Considerations and Conclusionmentioning

confidence: 99%

“…MX69 binds to MDM2 and prevents the protein from interacting with the IRES of XIAP mRNA which results in decreased XIAP translation and MDM2 degradation. The authors also show that MX69 has no effect on normal human hematopoiesis cells in vitro and is well tolerated in animal models [ 122 , 123 ] while MX3 showed increased heart tissue damage, elevation of alanine aminotransferase (ALT), and decreased white blood cells in an animal model [ 122 ].…”

Section: Therapeutic Considerations and Conclusionmentioning

confidence: 99%

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The Role of MDM2 in Promoting Genome Stability versus Instability

Saadatzadeh

Elmi

Pandya³

et al. 2017

IJMS

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In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein–protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.

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Mdm2-RNA Interactions as a Target for Cancer Therapy: It’s Not All About p53

Cited by 6 publications

References 11 publications

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

The Role of MDM2 in Promoting Genome Stability versus Instability

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