Disease relevance of Mdm2

• Mice lacking Mdm2 in the CNS developed hydranencephaly at embryonic day 12.5 due to apoptosis, whereas Mdm4 deletion showed a proencephaly phenotype at embryonic day 17.5 because of cell cycle arrest and apoptosis [1].
• Thus, we assessed whether the expression of deltagamma1 affects irradiation-induced phosphorylation of Mdm2 and radioresistance of melanoma cells by perturbing the regulation of p53 [2].
• Immunohistochemical analysis for Mdm2 and p53 proteins in methylcholanthrene-induced mouse rhabdomyosarcomas [3].
• Many Emu-myc lymphomas sustained either p53 (28%) or ARF (24%) loss of function, whereas Mdm2 levels were elevated in others [4].
• Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers [5].

High impact information on Mdm2

• Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53 [6].
• Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction [7].
• In primary cells, Raf also activates the Mdm2 inhibitor p19ARF [7].
• During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss [8].
• Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein [9].

Chemical compound and disease context of Mdm2

• In this study, we show that hypoxia induces down-regulation of Mdm2 as well as serine 15 phosphorylation and nuclear accumulation of p53 in cultured cortical neurons from E16 mice [10].
• Our data indicate that Mdm2 inhibitors may be an effective means of selectively targeting colon cancers that retain a sequence-normal p53 gene while sparing normal tissue and that the AOM model is an appropriate model for the preclinical development of these drugs [11].

Biological context of Mdm2

• Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis [12].
• Additionally, Mdm2 and Mdm4 had a gene dosage effect, because loss of three of the four Mdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone [1].
• In addition, activation of PKB correlated with Mdm2 phosphorylation and stability in a variety of human tumor cells [13].
• Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair [14].
• Mice deleted for either Mdm2 or Mdm4 die during embryogenesis, and the developmental lethality of either mouse model can be rescued by concomitant deletion of p53 [15].

Anatomical context of Mdm2

• Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development [1].
• The interaction between p19(Arf) and NPM occurs in primary mouse embryonic fibroblasts, including those lacking both Mdm2 and p53 [16].
• Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane [17].
• Loss of p19ARF enhances the defects of Mdm2 overexpression in the mammary gland [18].
• The Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells [19].

Associations of Mdm2 with chemical compounds

• In order to address the issue of how these modifications might regulate Mdm2 function, putative phosphorylation sites within this domain were substituted, individually or in pairs, with alanine residues [20].
• Cellular localization and co-immunoprecipitation experiments using a cell line derived from an AOM-induced colon tumor (AJ02-NM(0) cells) pointed to constitutively expressed Mdm2 as being an important negative regulator of p53 in these cells [11].
• We tested the response of AJ02-NM(0) cells to the recently developed Mdm2 inhibitor, Nutlin-3 [11].
• ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage [21].
• A role for the polyproline domain of p53 in its regulation by Mdm2 [22].

Physical interactions of Mdm2

• The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression [23].

Enzymatic interactions of Mdm2

• Recently, B56gamma subunit-containing PP2A holoenzymes have shown to dephosphorylate Mdm2, a negative regulator of p53 [2].

Co-localisations of Mdm2

• Arf and Mdm2 co-localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence [24].

Regulatory relationships of Mdm2

• Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo [25].
• A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance [2].
• Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis [26].
• p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons [10].

Other interactions of Mdm2

• The protein encoded by the murine double minute 2 (Mdm2) gene inactivates the function of the tumor suppressor p53 [18].
• Constitutive overexpression of Mdm2 and Cdk4 mRNAs was found, which might have contributed to the loss of G1 arrest [27].
• Recent data show that cyclin G1 can regulate the levels of p53 by a mechanism that involves dephosphorylation of Mdm2 by protein phosphatase 2A [28].
• Mice lacking Mdm2 in the heart were embryonic lethal and showed defects at the time recombination occurred [29].
• Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation [30].

Analytical, diagnostic and therapeutic context of Mdm2

• Western blot analyses revealed that irradiated COS-7 and NIH3T3 cells stably expressing deltagamma1 showed significantly less irradiation-induced Mdm2 phosphorylation [2].
• We analyzed Mdm2 expression between 7.5 and 9 days post-coitum (dpc) by whole-mount in situ hybridization and report here a novel expression pattern during neural crest development [31].
• Surprisingly, microinjection of Mdm2 mRNA in two-cell-stage embryos led to inhibition of cellular convergence during gastrulation [32].
• Quantitative RT-PCR analysis revealed no increased mRNA levels in TCDD-treated rats, but immunohistological studies indicated that TCDD modulated Mdm2 protein levels, and in particular, increased nuclear levels in rat hepatocytes in situ [33].
• Finally, immunofluorescence experiments showed that both p63 isoforms were localized in the nucleus and could be exported when coexpressed with Mdm2 but not with MdmX [34].

References