Mdm2 binds p73α without targeting degradation

Bálint, Éva; Bates, Stewart; Vousden, Karen H.

doi:10.1038/sj.onc.1202781

Cited by 200 publications

(174 citation statements)

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“…55 p73 is also able to bind to MDM-2, but is not degraded and so cannot be stabilised by ARF expression. 56 This provides a direct mechanism for E2F-1-induced cell death, and although p73 is not frequently mutated in human tumours, methylation-dependent silencing has been reported in haematological malignancies. 57 Moreover, it has recently been shown that several tumour-derived mutants of p53 that are often retained in cancer are able to bind and inactivate p73, thereby circumventing the necessity to mutate p73 per se.…”

Section: A Role In Cancermentioning

confidence: 99%

Life and death decisions by E2F-1

2003

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Deregulation of the transcription factor E2F-1 is a common event in most human cancers. Paradoxically, E2F-1 has been shown to have the ability to induce both cell cycle progression and programmed cell death, leading potentially to both tumour-promoting as well as tumour-suppressive effects. Although the pathway to cell cycle progression seems straightforward with a number of growth-promoting E2F target genes having been described, the pathways to apoptosis are less well defined and more complex. The discovery that E2F-1 'knockout' mice are highly tumour prone has caused a recent surge in the number of reports relating to programmed cell death. This review focuses on these recent findings, highlighting the way in which they have increased our understanding of E2F-1-induced cell death, as well as indicating the questions that remain. Insight gained as to the role of this intriguing molecule in cancer and its potential for targeted therapy will also be discussed.

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Section: A Role In Cancermentioning

confidence: 99%

Life and death decisions by E2F-1

2003

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“…HDM2 has also been shown to functionally interact with other proteins including p14ARF, Rb, E2F-1 (Iwakuma and Lozano, 2003) and p21 (Zhang et al, 2004). Furthermore, when overexpressed, HDM2 also binds to other p53 family members p73 (Balint et al, 1999) and p63 (Kadakia et al, 2001). Like p53, p73 binds to the N-terminal TA domain of HDM2 resulting in suppression of p73 transcriptional activity (Balint et al, 1999;Zeng et al, 1999).…”

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confidence: 99%

“…Furthermore, when overexpressed, HDM2 also binds to other p53 family members p73 (Balint et al, 1999) and p63 (Kadakia et al, 2001). Like p53, p73 binds to the N-terminal TA domain of HDM2 resulting in suppression of p73 transcriptional activity (Balint et al, 1999;Zeng et al, 1999). HDM2 mutants lacking amino acid residues 58-89 do not interact with either p53 or p73, suggesting that both p53 and p73 bind to a similar region at the N-terminus of HDM2 (Balint et al, 1999).…”

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confidence: 99%

“…Like p53, p73 binds to the N-terminal TA domain of HDM2 resulting in suppression of p73 transcriptional activity (Balint et al, 1999;Zeng et al, 1999). HDM2 mutants lacking amino acid residues 58-89 do not interact with either p53 or p73, suggesting that both p53 and p73 bind to a similar region at the N-terminus of HDM2 (Balint et al, 1999). In addition, HDM2 also binds to p53 through the central domain of HDM2 (Wallace et al, 2006).…”

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confidence: 99%

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HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function

et al. 2007

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Nutlin-3, a small molecule inhibitor, activates p53 by disrupting p53-HDM2 association. In this study, we found that Nutlin-3 suppressed cell growth and induced apoptosis in the absence of wild-type p53, suggesting a p53-independent mechanism for Nutlin-3-induced cell death. Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. We demonstrate that Nutlin-3 inhibits endogenous binding between the proapoptotic p73 isoform TAp73a and HDM2 in p53-null cells. Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. p73 knockdown by siRNA results in rescue of Nutlin-3-treated cells, indicating that Nutlin-3-induced apoptosis is, at least in part, p73 dependent. In addition, Nutlin-3 treatment increases TAp73a protein levels with prolongation of p73 half-life. These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated.

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“…While p53 is degradated by binding to its E3 ligase MDM2, MDM2 binding to p73 disrupts its interaction with p300/CBP, but does not mediate p73 degradation. [20][21][22] Instead, p73 degradation is linked to SUMO-1 modification which renders it proteasomedegradable. 23 It is possible that hetero-oligmerization prevents sumoylation of p73, thereby stabilizing it.…”

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confidence: 99%