MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MDM2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent proteasome pathway in the absence of p53. When HL-60 cells, p53 null, were treated with etoposide, MDM2 was markedly decreased prior to caspase-3-dependent retinoblastoma tumo...

Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions....

Mdm2 (murine double minute 2)-mediated ubiquitination of the p53 tumour suppressor requires interaction of the ligase at two distinct binding sites that form general multiprotein-docking sites for the p53 protein. The first Mdm2-binding site resides in the transactivation domain of p53 and is an allosteric effector site for Mdm2-mediated p53 ubiquitination; the second site requires the acid dom...

The mdm2 oncogene has transforming potential that is activated by overexpression. We previously reported the identification of human choriocarcinoma cell lines that have very high levels of mdm2 proteins as well as elevated levels of a stabilized wild-type p53 protein. Importantly, this mdm2 overexpression resulted from enhanced translation of mdm2 mRNA, a mechanism that had not previously been...

MDM2 protein is thought to exhibit tumorigenic activity by binding to the p53 tumor-suppressor protein and inhibiting its function. Alternatively, MDM2 may have oncogenic roles other than those resulting from p53 interactions. Here we report that MDM2 can induce expression of the p65 subunit of NF-kappaB, which is an anti-apoptotic factor expressed in certain neoplastic cells in response to che...

BACKGROUND The p53 tumor suppressor protein is mainly regulated by alterations in the half-life of the protein, resulting in significant differences in p53 protein levels in cells. The major regulator of this process is Mdm2, which ubiquitinates p53 and targets it for proteasomal degradation. This process can be enhanced or reduced by proteins that associate with p53 or Mdm2 and several protein...

The tumor suppressor protein p53 is a transcription factor that induces G1 arrest of the cell cycle and/or apoptosis. The murine double-minute protein MDM2 and its homologue MDM4 (also known as MDMX) are critical regulators of p53. Altered transcripts of the human homologue of mdm2, MDM2 , have been identified in human tumors, such as invasive carcinoma of the breast, lung carcinoma, and liposa...

Genotoxic stress activation of the tumor suppressor transcription factor p53 involves post-translational C-terminal modifications that increase both protein stability and DNA binding activity. We compared the requirement for p53 protein activation of p53 target sequences in two major p53-regulated genes, p21/WAF1 (encoding a cell cycle inhibitory protein) and Mdm2 (encoding a ubiquitin ligase t...

The tumor suppressor p53 is a potent transcription factor of which the ability to mediate transcription is inhibited through an interaction with the oncoprotein mouse double minute 2 (Mdm2). The present study has tested the hypothesis that Mdm2 inhibits the p53 response in normally growing cells by binding to chromatin-associated p53. Using chromatin immunoprecipitation, we show that Mdm2 local...

The murine double minute-2 (Mdm2) oncoprotein is an E3 ligase and a key regulator of a variety of fundamental cellular processes [1]. Mdm2 was originally identified as being amplified on double-minute chromosomes in transformed mouse fibroblasts [2]. Soon after its discovery, Mdm2 was found to be a negative regulator of tumor suppressor p53. The importance of Mdm2 in controlling the p53 activit...