p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

Wasylyk, Christine; Salvi, Roberto; Argentini, Manuela; Dureuil, Christine; Delumeau, Isabelle; Abecassis, Joseph; Debussche, Laurent; Wasylyk, Bohdan

doi:10.1038/sj.onc.1202528

Cited by 112 publications

(87 citation statements)

References 87 publications

(82 reference statements)

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“…In contrast, other studies using HDM-2-binding molecules including p53 peptides attached to membrane-penetrating sequences on their amino terminal ends and small molecules that block the p53-HDM-2 interaction found that these agents induce p53-dependent apoptosis of cancer cells (6)(7)(8)(9)(10)(11). However, our observations were consistent with the results from a 2D NMR study on the structure of PNC-27 showing that this peptide adopts a strongly amphipathic alpha-helix-loop-alpha-helix structure (12) observed in membrane-active peptides (13,14).…”

Section: Hdm-2 Binding | Membranolysis | Three-dimensional Structure mentioning

confidence: 73%

Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Sarafraz-Yazdi

Bowne

Adler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The anticancer peptide PNC-27, which contains an HDM-2-binding domain corresponding to residues 12-26 of p53 and a transmembrane-penetrating domain, has been found to kill cancer cells (but not normal cells) by inducing membranolysis. We find that our previously determined 3D structure of the p53 residues of PNC-27 is directly superimposable on the structure for the same residues bound to HDM-2, suggesting that the peptide may target HDM-2 in the membranes of cancer cells. We now find significant levels of HDM-2 in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines. In colocalization experiments, we find that PNC-27 binds to cell membrane-bound HDM-2. We further transfected a plasmid expressing full-length HDM-2 with a membrane-localization signal into untransformed MCF-10-2A cells not susceptible to PNC-27 and found that these cells expressing full-length HDM-2 on their cell surface became susceptible to PNC-27. We conclude that PNC-27 targets HDM-2 in the membranes of cancer cells, allowing it to induce membranolysis of these cells selectively.

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Section: Hdm-2 Binding | Membranolysis | Three-dimensional Structure mentioning

confidence: 73%

Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Sarafraz-Yazdi

Bowne

Adler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In both cases, p53 is highly induced and showed a negative correlation with E2F1 expression. The p53 dependence for the interaction between E2F1 and MDM2 was first suggested by Wasylyk et al (1999). This group showed that IP3, a peptide with a sequence resemblance to p53 but with a 100-fold greater affinity for MDM2, induced a decrease Figure 5 Nutlin-3a inhibits binding of E2F1 to MDM2 and increases E2F1 activity after DNA damage in p53 mutant cells.…”

Section: Discussionmentioning

confidence: 92%

“…The mdm2 gene is itself transcriptionally activated by p53 in a regulatory feedback loop (Bond et al, 2005). Several strategies have been explored to disrupt the p53-MDM2 interaction, including the use of small peptides (Wasylyk et al, 1999), antisense oligonucleotides (Bianco et al, 2005) and inhibitors of MDM2 ubiquitin ligase .…”

Section: Introductionmentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

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MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

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“…These cells express wild type p53, as determined in a yeast functional assay and by sequencing the coding exons (Millon et al, in preparation). In addition, expression of ARF and the IP3 peptide, which stabilize p53 (Sherr, 1998;Wasylyk et al, 1999), resulted in growth arrest of the transfected cells (data not shown). We concluded that RPMI2650 cell line is a useful model to investigate the e ects of MDM2 on endogenous active wild type p53.…”

Section: Mdm2mentioning

confidence: 95%

The contribution of the RING finger domain of MDM2 to cell cycle progression

Argentini¹,

Barboule²,

Wasylyk³

2000

Oncogene

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The MDM2 oncoprotein binds to p53 and abrogates p53-mediated G1 arrest and apoptosis. We show that MDM2 over-expression accelerates cell cycle progression of RPMI2650 cells by overcoming the negative e ect of endogenous wild type p53 at the G1/S checkpoint. The interaction with p53 and transcription inhibition are necessary but not su cient. The RING ®nger domain of MDM2 is also required for the positive e ect of MDM2 on the cell cycle. Surprisingly, several point mutants in the zinc binding sites of the RING ®nger are fully competent for cell cycle stimulation even though they abolish MDM2-directed degradation of p53 and MDM2 E3-ligase activity. In contrast, alterations in and around the cryptic nucleolar localization sequence (KR motif) inhibit MDM2-mediated cell cycle progression as well as p53 degradation and MDM2 E3 ligase activity. We found that all the RING mutants decrease inhibition of both p53 dependent reporters and endogenous p21 CIP1/WAF1/SDI1 . These results indicate that the RING ®nger of MDM2 has a role in the regulation of the cell cycle that is independent of p53 degradation and endogenous p21 CIP1/WAF1/SDI1 regulation. Oncogene (2000) 19, 3849 ± 3857.

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p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

Cited by 112 publications

References 87 publications

Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

The contribution of the RING finger domain of MDM2 to cell cycle progression

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