HDM2 is a p53-specific E3 ubiquitin ligase. Its overexpression leads to excessive inactivation of tumor protein p53, diminishing its tumor suppressor function. HDM2 also affects the cell cycle, apoptosis and tumorigenesis through interacting with other molecules, including several ribosomal proteins. To identify novel HDM2 regulators, we performed a yeast two-hybrid screening using HDM2 as bait...

HDM2 binds to the p53 tumour suppressor and targets it for proteosomal degradation. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2 and abrogates its repressive function. Using a novel in vitro selection methodology, we simulated the emergence of resistance by evolving HDM2 mutants capable of binding p53 in the presence of Nutlin concentrations that inhibi...

Inactivation of the p53 transcription factor by mutation or other mechanisms is a frequent event in tumorigenesis. One of the major endogenous negative regulators of p53 in humans is hDM2, a ubiquitin E3 ligase that binds to p53 causing proteasomal p53 degradation. In this work, a library of organometallic iridium(III) compounds were synthesized and evaluated for their ability to disrupt the p5...

The inhibitors of p53-HDM2 interaction are attractive molecules for the treatment of wild-type p53 tumors. In order to search more potent HDM2 inhibitors, docking operation with CDOCKER protocol in Discovery Studio 2.1 (DS2.1) and multidimensional hybrid quantitative structure-activity relationship (QSAR) studies through the physiochemical properties obtained from DS2.1 and E-Dragon 1.0 as desc...

Hdm2 and HdmX coordinately regulate the stability and function of p53. Each is overexpressed in subsets of many different types of malignancy, and most of these subsets maintain wild-type p53. Nutlins, newly discovered small-molecule inhibitors of the Hdm2-p53 interaction, offer a novel strategy for therapy of tumors with wild-type p53. We now show that Nutlin-3 efficiently induces apoptosis an...

Yin Yang 1 (YY1) is a transcription factor that plays an essential role in development. However, the full spectrum of YY1's functions and mechanism of action remains unclear. We find that YY1 ablation results in p53 accumulation due to a reduction of p53 ubiquitination in vivo. Conversely, YY1 overexpression stimulates p53 ubiquitination and degradation. Significantly, recombinant YY1 is suffic...

The glucocorticoid receptor (GR) and the tumor suppressor p53 mediate different stress responses. We have studied the mechanism of their mutual inhibition in normal endothelial cells (HUVEC) in response to hypoxia, a physiological stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimulates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia a...

The inhibitors of p53-HDM2 interaction are attractive molecules for the treatment of wild-type p53 tumors. In order to search more potent HDM2 inhibitors, docking operation with CDOCKER protocol in Discovery Studio 2.1 (DS2.1) and multidimensional hybrid quantitative structure-activity relationship (QSAR) studies through the physiochemical properties obtained from DS2.1 and E-Dragon 1.0 as desc...

Translationally Controlled Tumour Protein (TCTP), a highly conserved protein present in all eukaryotic organisms, has a number of intracellular and extracellular functions including an anti-apoptotic role. TCTP was recently shown to interact with both p53 and HDM2, inhibiting auto-ubiquitination of the latter and thereby promoting p53 degradation. In this study, we further investigated the inte...

the inhibitors of p53-hdm2 interaction are attractive molecules for the treatment of wild-type p53 tumors. in order to search more potent hdm2 inhibitors, docking operation with cdocker protocol in discovery studio 2.1 (ds2.1) and multidimensional hybrid quantitative structure-activity relationship (qsar) studies through the physiochemical properties obtained from ds2.1 and e-dragon 1.0 as desc...