The tumor suppressor protein p53 is a transcription factor that induces G(1) 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 lipos...

The MDM2 protein targets the p53 tumor suppressor for ubiquitin-dependent degradation [1], and can function both as an E3 ubiquitin ligase [2] and as a regulator of the subcellular localization of p53 [3]. Oncogene activation stabilizes p53 through expression of the ARF protein (p14(ARF) in humans, p19(ARF) in the mouse) [4], and loss of ARF allows tumor development without loss of wild-type p5...

Rapamycin, a potential anti-cancer agent, modulates activity of various factors functioning in translation, including eIF4E, an initiation factor selectively regulating expression of a subset of cellular transcripts. We show here that rapamycin suppresses levels of the p53-regulator MDM2 by translational inhibition without affecting mdm2 mRNA expression or protein stability. Rapamycin inhibits ...

Murine double minute 2 (Mdm2) is known to enhance the transactivation potential of human immunodeficiency virus (HIV-1) Tat protein by causing its ubiquitination. However, the regulation of Mdm2 during HIV-1 infection and its implications for viral replication have not been well studied. Here, we show that the Mdm2 protein level increases during HIV-1 infection and this effect is mediated by HI...

p53 can be regulated through post-translational modifications and through interactions with positive and negative regulatory factors. MDM2 binding inhibits p53 and promotes its degradation by the proteasome, whereas promyelocytic leukemia (PML) activates p53 by recruiting it to multiprotein complexes termed PML-nuclear bodies. We reported previously an in vivo and in vitro interaction between P...

The MDM2 oncoprotein encodes a 90 kDa nuclear phosphoprotein capable of abrogating the growth suppressive functions of p53 and pRb tumor suppressor proteins by direct interaction. Alternative splicing of MDM2 protein coding sequences has been documented during tumor progression in human ovarian and bladder carcinomas. The aim of this study was to determine whether alternative splicing of MDM2 o...

The MDM2 oncogene has been suggested as a molecular target for treating human cancers, including breast cancer. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. The present study was designed to develop a new class of MDM2 inhibitors that exhibit anticancer activity in MDM2...

We have demonstrated previously that the oncoprotein Mdm2 has a ubiquitin ligase activity for the tumor suppressor p53 protein. In the present study, we characterize this ubiquitin ligase activity of Mdm2. We first demonstrate the ubiquitination of several p53 point mutants and deletion mutants by Mdm2. The point mutants, which cannot bind to Mdm2, are not ubiquitinated by Mdm2. The ubiquitinat...

Covalent attachment of SUMO-1 to Mdm2 requires the activation of a heterodimeric Aos1-Uba2 enzyme (ubiquitin-activating enzyme (E1)) followed by the conjugation of Sumo-1 to Mdm2 by Ubc9, a protein with a strong sequence similarity to ubiquitin carrier proteins (E2s). Upon Sumo-1 conjugation, Mdm2 is protected from self-ubiquitination and elicits greater ubiquitin-protein isopeptide ligase (E3)...

The Epstein-Barr virus (EBV) lytic program elicits ATM-dependent DNA damage response, resulting in phosphorylation of p53 at N-terminus, which prevents interaction with MDM2. Nevertheless, p53-downstream signaling is blocked. We found here that during the lytic infection p53 was actively degraded in a proteasome-dependent manner even with a reduced level of MDM2. BZLF1 protein enhanced the ubiq...