NIR (novel INHAT repressor) can bind to p53 at promoters and inhibit p53-mediated gene transactivation by blocking histone acetylation carried out by p300/CBP. Like NIR, the E3 ubiquitin ligase MDM2 can also bind and inhibit p53 at promoters. Here, we present data indicating that NIR, which shuttles between the nucleolus and nucleoplasm, not only binds to p53 but also directly to MDM2, in part ...

MDM2 and MDM4, a structurally related MDM2 homolog, negatively regulates expression and functions of TP53 tumor suppressor gene. To explore the precise expression patterns and function of MDM2 and MDM4 in wild-type (wt) TP53 cancer cells, we analyzed 11 various cancer cell lines with wt TP53. All cell lines exhibited deregulated expression of MDM2 and MDM4, and were divided into two distinct ty...

The MDM2-p53 pathway has a prominent oncogenic function in the pathogenesis of various cancers. Nutlin-3, a small-molecule antagonist of MDM2-p53 interaction, inhibits proliferation in cancer cells with wild-type p53. Herein, we evaluate the expression of MDM2, both the full length and a splicing variant MDM2-A, and the sensitivity of Nutlin-3 in different cancer cell lines. Included are seven ...

MDM2 inhibits transactivation properties of the tumor suppressor protein p53 by binding to and facilitating proteasomal degradation of p53. Because MDM2 targets p53 for degradation, it was anticipated that cells that overexpress MDM2 would not contain functional wild-type p53 (wtp53). However, p53 and MDM2 in cells with damaged DNA can become phosphorylated, and their binding to each other can ...

The MDM2 gene is a nuclear phosphoprotein that is regulated by p53 and functions, in one capacity, to inhibit the transcriptional activity of the wild-type p53 protein. Multiple MDM2 transcripts were detected in human breast epithelial cells. In estrogen receptor-negative normal, immortal, and tumorigenic breast epithelial cells, we found a good correlation between MDM2 mRNA levels and expressi...

Mdm2 can mediate p53 ubiquitylation and degradation either in the form of the Mdm2 homodimer or Mdm2/MdmX heterodimer. The ubiquitin ligase activity of these complexes resides mainly in their respective RING finger domains and also requires adjacent C-terminal tails. So far, structural studies have failed to show significant differences between Mdm2 RING homodimers and Mdm2/MdmX RING heterodime...

Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53. Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models. The tissue-specific deletion of Mdm2 induces p53-dependent apoptosis, whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest. Compared to Mdm4 deletion, Mdm2 deletion causes more seve...

Our previous study shows that MDM2, a negative feedback regulator of the tumor suppressor p53, inhibits p300-mediated p53 acetylation. Because PCAF (p300/CREB-binding protein-associated factor) also acetylates and activates p53 after DNA damage, in this study we have examined the effect of MDM2 on PCAF-mediated p53 acetylation. We have found that MDM2 inhibited p53 acetylation by PCAF in vitro....

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...

The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcrip...