Dual-Site Regulation of MDM2 E3-Ubiquitin Ligase Activity

Wallace, Maura; Worrall, Erin G.; Pettersson, Susanne; Hupp, Ted R.; Ball, Kathryn L.

doi:10.1016/j.molcel.2006.05.029

Cited by 164 publications

(260 citation statements)

References 26 publications

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“…3B). Interestingly, even though the BRET 50 does not change much, there is still a specific BRET at 30 µM, indicating that p53 and HDM2 still interact, presumably through the reported second interface site [10].…”

Section: Resultsmentioning

confidence: 94%

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Using BRET to study chemical compound‐induced disruptions of the p53‐HDM2 interactions in live cells

Mazars

Fåhræus

2010

Biotechnology Journal

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Modification of protein‐protein interactions (PPIs) holds promise for novel rational drug design. Disrupting or modifying protein interactions offers new challenges in terms of chemical compound libraries and techniques for compound validation. As proteins interact with several partners in different allosteric conformation in a pathological and tissue‐specific fashion, it is difficult to predict the in vivo effect of PPI acting compounds identified by in vitro screening assays. It is therefore desirable to develop techniques that rapidly allow cell‐based validation of protein interacting compounds. The binding of the p53 tumor suppressor to the HDM2 E3 ubiquitin ligase is important for controlling p53 activity, and several compounds, such as Nutlin‐3, have been designed to bind a hydrophobic pocket in the N‐terminus of HDM2 to prevent the interaction with p53 to stabilize and activate downstream p53 pathways. We have used the p53‐HDM2 interaction as a model system to explore the bioluminescence resonance energy transfer (BRET) technique for validating compounds that disrupt PPIs in living cells.

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Section: Resultsmentioning

confidence: 94%

“…It has been reported that p53-HDM2 consists of two interfaces [10]. The first is the well-known N-termini target for Nutlin-3 in which the Box I domain of p53 fits into a hydrophobic pocket of HDM2.…”

Section: Discussionmentioning

confidence: 99%

Using BRET to study chemical compound‐induced disruptions of the p53‐HDM2 interactions in live cells

Mazars

Fåhræus

2010

Biotechnology Journal

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“…MDM2 recognizes a short region in the TA domain of p53 and interferes with its transcriptional activity; at the same time, MDM2 interacts with the DBD region and ubiquitinates p53, promoting its proteasomal degradation. 33,34 As MDM2 is a transcriptional target of p53, inhibition by MDM2 is part of a negative feedback loop on p53 activation. 34 In addition to MDM2, p53 is also bound and regulated by the MDM2-related protein MDMX (also named MDM4).…”

Section: Mdm2mentioning

confidence: 99%

p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

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The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53. The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway. Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73. Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects. In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment.

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“…Together, these observations suggest subtle but significant differences in the structure and regulation of p53-MDM2 and p53-MDM4 interfaces. Furthermore, recent studies have indicated a more complex regulation for p53-MDM2 interactions: the binding of the N-terminal domain of MDM2 with p53 BoxI may promote conformational changes in MDM2 to stabilize interaction of the MDM2 acidic domain with the p53 DNA binding domain (in a p53 region comprising β-sheets S9-S10 and the conserved BoxV; Wallace et al, 2006). Whether or not the MDM4 acidic region may also interact with the p53 DNA binding domain is presently unknown.…”

Section: Protein Structuresmentioning

confidence: 99%

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

215

162

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The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification / overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity.

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Dual-Site Regulation of MDM2 E3-Ubiquitin Ligase Activity

Cited by 164 publications

References 26 publications

Using BRET to study chemical compound‐induced disruptions of the p53‐HDM2 interactions in live cells

Using BRET to study chemical compound‐induced disruptions of the p53‐HDM2 interactions in live cells

p53-family proteins and their regulators: hubs and spokes in tumor suppression

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

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