IndraLab

"Currently, how FL118 changes the biochemical properties of Mdm2–MdmX E3 complex remains an open question, even though it can be partially explained by FL118 slightly decreasing Hdm2–p53 interaction and moderately increasing Hdm2–HdmX interaction ( xref )."

"As a transcription factor, p53 can bind to the promoter region of the mdm2 gene to promote transcription of Mdm2 mRNA [ xref , xref ]."

"There is great interest in molecules capable of inhibiting the interactions between p53 and its negative regulators hDM2 and hDMX, as these molecules have validated potential against cancers in which one or both oncoproteins are overexpressed."

"Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult."

"It interacts with p53, Hdm2 and Hdmx, and its deubiquitinating function towards these proteins protects cells from apoptosis [ xref , xref ]."

"To engineer the cyclotide MCoTI-I for antagonizing protein-protein interactions between p53 and Hdm2 or HdmX we used the phage-selected α-helical peptide PMI ( xref ). xref This peptide conserves the residues Phe19, Trp23 and Leu26 of p53 required for the interaction with Hdm2 and HdmX, and is able to bind the p53 binding domains of Hdm2 and Hdmx with low nM affinity. xref The PMI peptide was grafted onto the cyclotide scaffold using loop 6."

"Changes in chemical shifts are concentrated around loop 6, which accommodates the PMI peptide segment required for the interaction with the p53-binding domains of Hdm2 and HdmX."

"Thus, the interactions between p53, Hdm2 and HdmX are critical for complete regulation of p53 [ xref ]."

"Here, we describe the use of a genetic selection system and encoded library of conformationally preorganized peptides to perform functional profiling of each regulator revealing specific recognition features that guide the antagonism of Hdm2–p53 and Hdmx–p53 interactions."

"In conclusion, this research describes the implementation of the high-throughput conditional transcription system to profile the functional elements important for the antagonism of Hdm2–p53 and Hdmx–p53 interactions, implicated as causative events in a large proportion of human malignancies."

"Here we illustrate how the p53-Mdm2 protein-protein and p53 mRNA-Mdm2 interactions affect Mdm2-mediated control of p53 expression using the Phe19Ala p53 mutant."

"There is great interest in molecules that inhibit interactions between p53 and its negative regulators hDM2 and hDMX, as these molecules have validated potential against cancers that overexpress one or both of these oncoproteins. xref , xref We reported that substituted β 3 -peptides can inhibit these interactions xref , xref and, more recently, that minimally cationic β 3 -peptides are sufficiently cell permeable to upregulate p53-dependent genes in live cells. xref , xref These observations, coupled with the established intracellular stability of β-peptides xref – xref and the recently reported structures of hDM2 xref and hDMX, xref motivated us to exploit computational methods to identify β-peptides with improved potency and/or selectivity."

"Given that both Hdm2 and HdmX bind to the transactivation domain of p53, targeting both p53-binding domains has been shown to be critical for the activation of the p53 tumor suppressor in cancer cells overexpressing Hdm2 and/or HdmX. xref In agreement with this, the cyclotide MCo-PMI was able to reactivate the p53 tumor suppressor pathway in different cancer lines expressing different levels of Hdm2 and/or HdmX and was not cytotoxic to non-cancer cells or cancer cells with disfunctional p53."

"Here we show that disruption of p53-mdm2 binding using the MDM2-specific inhibitor Nutlin activates p53 in TGCT cells and is sufficient to induce strong apoptosis."

"To determine whether FL118 treatment affects Hdm2–p53 and Hdm2–HdmX physical interaction, we performed coimmunoprecipitation experiments after treating cells with 10 nmol/L FL118 in the presence of MG132 to block p53 and MdmX degradation."

"Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway."

"Compounds broadly classified as chalcones have been shown to exhibit anticancer activity through multiple mechanisms, including disruption of p53 interactions with MDM2 or HDM2, xref , xref inhibition of p-glycoprotein, xref – xref and disruption of microtubule polymerization. xref – xref Many of the latter compounds were designed as analogs of colchicine and combretastatins, natural products known to bind β-tubulin."

"In addition, phosphorylation of MDM2 by ATM also reduces the affinity of the central acidic domain for p53, suggesting that ATM phosphorylation may also impact the p53–MDM2 interaction by affecting the conformation of the MDM2 protein ( xref )."

"However, Hdmx does not relieve the inhibition by Mdm2 of transcription activation by p53, probably due to the formation of a trimeric complex consisting of Hdmx, Mdm2, and p53."

"Genetic system for monitoring Hdm2–p53 and Hdmx–p53 interactions."