The p53 tumor suppressor gene is inactivated in human tumors by several distinct mechanisms. The best characterized inactivation mechanisms are: (i) gene mutation; (ii) p53 protein association with viral proteins; (iii) p53 protein association with the MDM2 cellular oncoprotein. The MDM2 gene has been shown to be abnormally up-regulated in human tumors and tumor cell lines by gene amplification...

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...

Pre-neoplastic lesions in rodent liver often express high levels of MDM2 and lack a p53 response to DNA damage. The question we posed was whether there is a liver-specific regulation of the p53/MDM2 feedback loop and if it can be related to the development of pre-neoplastic lesions, referred to as enzyme altered foci (EAF) in rats. Acute responses of p53 and MDM2 to diethylnitrosamine (DEN) wer...

PURPOSE: MDM2 is a key negative regulator of the p53 signaling pathway. We aimed to evaluate the inter-relationships between MDM2 SNP309, mRNA expression, amplification, and TP53 mutations, as well as their correlations with responsiveness to MDM2 inhibitors and other commonly used cytotoxic drugs tested in the NCI-60 cancer cell panel. EXPERIMENTAL DESIGN: SNP309 was genotyped in the NCI-60 ca...

Levels of the p53 tumor suppressor protein are increased in human cytomegalovirus (HCMV)-infected cells and may be important for HCMV pathogenesis. In normal cells p53 levels are kept low due to an autoregulatory feedback loop where p53 activates the transcription of mdm2 and mdm2 binds and ubiquitinates p53, targeting p53 for proteasomal degradation. Here we report that, in contrast to uninfec...

BACKGROUND Malignant melanoma is the most invasive cutaneous tumor which is associated with an incredibly high mortality rate. The most reliable histological factors associated with melanoma prognosis are tumor thickness- measured by the Breslow index- and invasion depth- measured by Clark level. Murine double minute 2 (MDM2) gene inhibits p53-dependent apoptosis. An increase in MDM2 expression...

The protein p73, a homologue of the tumor suppressor protein p53, is capable of inducing apoptosis and cell cycle arrest. MDM2 is transcriptionally activated by p73 and represses the functions of p73, including p73-dependent transactivation and growth suppression. However, the molecular mechanism of this repression is unknown. In this study, we show that MDM2 mediates p73 ubiquitination. MDM2 m...

Berberine, a natural product derived from a plant used in Chinese herbal medicine, is reported to exhibit anticancer effects; however, its mechanism of action is not clearly defined. Herein, we demonstrate that berberine induces apoptosis in acute lymphoblastic leukemia (ALL) cells by downregulating the MDM2 oncoprotein. The proapoptotic effects of berberine were closely associated with both th...

The Cancer Genome Atlas (TCGA) data indicate that high MDM2 expression correlates with all subtypes of breast cancer. Overexpression of MDM2 drives breast oncogenesis in the presence of wild-type or mutant p53 (mtp53). Importantly, estrogen-receptor positive (ER+) breast cancers overexpress MDM2 and estrogen mediates this expression. We previously demonstrated that this estrogen-MDM2 axis activ...

Tumor suppressor p53 plays a central role in preventing tumor formation. The levels and activity of p53 is under tight regulation to ensure its proper function. Murine double minute 2 (MDM2), a p53 target gene, is an E3 ubiquitin ligase. MDM2 is a key negative regulator of p53 protein, and forms an auto-regulatory feedback loop with p53. MDM2 is an oncogene with both p53-dependent and p53-indep...