p53 and Adhesion
Transcript of p53 and Adhesion
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p53
Ability to prevent undue cell proliferation
Plays a critical role in the host and tumor
response to radiation and chemotherapy
It seems that p53 can be selectively
reactivated in tumor cells target for gene
therapy
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In vivo activation of the p53 pathway by small-molecule antagonists of MDM2
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, KongN, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu E
Science (2004)303: 844-848
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3 mechanisms to repress p53 by activation of MDM2-expression:
1. MDM2 binds p52 at transactivation domain and blocks its ability toacitvate transcription
2. MDM2 is involved in the nuclear export of p533. MDM2 serves as a ubiquitin ligase that promotes p53 degradation
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3 mechanisms to repress p53 by activation of MDM2-expression:
1. MDM2 binds p52 at transactivatin domain and blocks its ability toacitvate transcription
2. MDM2 is involved in the nuclear export of p533. MDM2 serves as a ubiquitin ligase that promotes p53 degradation
Mdm2gene is amplified or overexpressed in many human cancers
Activation of p53 pathway through inhibition of MDM2 has beenproposed as a novel therapeutic strategy
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Series of cis-imidazolineanalogs that were named
Nutlins (for Nutley inhibitor)
Mode of binding of Nutlin in
MDM2-p53 complex
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The treatment of cells with an inhibitor of MDM2-p53 binding shouldresult in
1. Stabilization and accumulation of p532. Activation of MDM2 expression3. Activation of other p53-regulated genes and p53 pathway
At cellular level: cell cycle arrest in G1 and G2 phases and/orapoptosis
Effect of MDM2 inhibitors on the cellular levelsof p53, MDM2 and p21
Mut p53 wt p53
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Nutlin-1 treatment induces theexpression of p21 gene but not the p53gene
Nutlins up-regulate p53 by meansof a posttranslational mechanism
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Cell cycle arrest of wt p53 cancer cell linesin G1 and G2 due to Nutlin-1
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Effect of Nutlin-1 on growth and viability of
cultured cancer cells
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Effect of Nutlin-3a and Nutlin-3b on expression of p21, MDM2 andp53 in wt p53 and mut p53-cells
Only Nutlin-3a activates expression of p21 and MDM2
Confirmation of the protein level by
Western blotting
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Effect of Nutlin-3a and -3b on growth and viability of wt p53 andmut53 cells
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Ability of Nutlin-3 to induce apoptosis in cancer cells withwt p53
After 48 hours Nutlin-3a incubation 45% of cell population showed
apoptosis
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In vivo antitumor activity of Nutlin-3
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SUMMARY
Nutlins are a class of stuctures with high potency andselectivity for reactivating p53 by inhibition of p53-MDM3
interaction Activity of Nutlins is dependent on p53 status There are two enantiomers of Nutlin-3. Activation of p53 and
apoptosis induction by Nutlin-3 is enantiomer specific
The data strengthen the notion that activation of p53 byinhibition of MDM2 binding is a potentially valuable strategyfor treating cancer