MDM2 and MDMX bind and stabilize the p53-related protein p73

Ongkeko, Weg M.; Wang, Xiaoqian; Siu, Wai Yi; Lau, Anita Wan Sze; Yamashita, Katsumi; Harris, Adrian L.; Cox, Lynne S.; Poon, Randy Y. C.

doi:10.1016/s0960-9822(99)80367-4

Cited by 118 publications

(93 citation statements)

References 39 publications

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“…Thus, it is plausible that Nutlin-3 could also disrupt the p73-HDMX complex. Although a physical interaction between exogenous p73 and HDMX has been described (Ongkeko et al, 1999;Wang et al, 2001), further studies will be required to determine whether p73 and HDMX form endogenous complexes in cancer cells and whether Nutlin-3 can disrupt this complex.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…40,41 MDM2 and MDMX also bind p73, but MDM2 does not promote p73 ubiquitination. 42,43 Rather, MDM2 relocalizes p73 to subnuclear speckles and represses p73 transcriptional activity by preventing its interaction with the acetyltransferase p300/CBP and RNA polymerase-associated factors. 44,45 Interestingly, MDM2 can also catalyze addition of the small ubiquitin-like protein NEDD8 to both p53 and p73, and also this modification inhibits their transcriptional activity.…”

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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“…Adenoviral or retroviral vectors have been used to re-introduce wild-type p53 into tumour cells with no or mutant p53, inducing apoptosis and promoting tumour regression in combination with radiation therapy in clinical trials Zeimet et al, 2000). Adenoviral expression of the p53 family members p63 or p73 was also able to induce apoptosis in certain cancer cells (Ishida et al, 2000), and since p73 is resistant to degradation by MDM2 and E6 (Marin et al, 1998;Prabhu et al, 1998;Balint et al, 1999;Dobbelstein et al, 1999;Ongkeko et al, 1999;Zeng et al, 1999), its potential for therapeutic application may be promising. In another approach, an adenovirus lacking the p53-inactivating oncogene E1B (Onyx-015) was shown to be able to replicate only in tumour cells that are defective in the p53 pathway, but not in normal cells, thus causing selective tumour cell killing and tumour regression in many patients (McCormick, 2000).…”

Section: Potential Of P53 In Cancer Therapymentioning

confidence: 99%

Activation and activities of the p53 tumour suppressor protein

Bálint¹,

Vousden²

2001

Br J Cancer

269

176

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The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress. One of the major regulators of p53 function is the MDM2 protein, and multiple forms of cellular stress activate p53 by inhibiting the MDM2-mediated degradation of p53. Mutations in p53, or disruption of the pathways that allow activation of p53, seem to be a general feature of all cancers. Here we review recent advances in our understanding of the pathways that regulate p53 and the pathways that are induced by p53, as well as their implications for cancer therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

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MDM2 and MDMX bind and stabilize the p53-related protein p73

Cited by 118 publications

References 39 publications

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

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

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

Activation and activities of the p53 tumour suppressor protein

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