The Many Faces of MDM2 Binding Partners

Riley, Maurisa F.; Lozano, Guillermina

doi:10.1177/1947601912455322

Cited by 55 publications

(62 citation statements)

References 163 publications

(174 reference statements)

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“…This observation indicates that Mdm2 gene amplification indeed results in its overexpression, but other mechanisms may also confer Mdm2 upregulation. Extensive studies have indicated that upregulation of Mdm2 results from elevated transcription, increased mRNA stability, enhanced translation and altered post-translational modification (reviewed in 22, 47). In addition, these mechanisms are associated with upregulation of Mdm2 in tumors.…”

Section: Elevated Levels Of Mdm Proteins In Human Tumorsmentioning

confidence: 99%

Molecular Pathways: Targeting Mdm2 and Mdm4 in Cancer Therapy

Qin

Lozano

2013

Clinical Cancer Research

164

157

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The p53 tumor suppressor is activated in response to cellular stresses to induce cell cycle arrest, cellular senescence, and apoptosis. The p53 gene is inactivated by mutations in more than 50% of human tumors. In addition, tumor cells dampen p53 activities via overexpression of p53 negative regulators, in particular two structurally related proteins Mdm2 and Mdm4. And yet, Mdm2 and Mdm4 possess p53-independent activities, which also contribute to tumor formation and progression. Given that Mdm2 and Mdm4 inhibit p53 activities to promote tumor development, small molecules and peptides were developed to abrogate the inhibition of p53 by Mdm proteins. Anti-tumor activities of these molecules have already been confirmed in preclinical studies and early-phase clinical trials. These research endeavors and clinical advances constitute the main focus of this review.

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Section: Elevated Levels Of Mdm Proteins In Human Tumorsmentioning

confidence: 99%

Molecular Pathways: Targeting Mdm2 and Mdm4 in Cancer Therapy

Qin

Lozano

2013

Clinical Cancer Research

164

157

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“…11 However, Mdm2 has also been shown to influence tumor phenotypes though p53-independent mechanisms. 12 For example, in CRC, several studies link the Mdm2 SNP309-G allele to exacerbated tumor phenotypes and increased overall risk, specifically in pre-menopausal women. 8,9 Importantly, this Mdm2 SNP309-G -associated risk is lost in women once they are post-menopausal.…”

Section: Introductionmentioning

confidence: 99%

Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

2014

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A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2(SNP309-G)) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2(SNP309-)(G) allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2(SNP309-)(G) allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2(SNP309-G/G) mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2(SNP309-G/G) colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERα and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2(SNP309-)(G) allele significantly impacts CRC through mechanisms outside the p53 pathway.

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“…[18][19][20] Numerous binding partners of Mdm2 and/or p53 influence their functional interaction and p53 activity. 1,21 One important example is the alternative reading frame (ARF) tumor suppressor encoded by the INK4a/ARF locus. 22 Oncogene activation and sustained DNA damage induce expression of ARF, which binds to Mdm2, inhibits its E3 ubiquitin ligase activity and restricts the p53 tumor suppressor is controlled by an interactive network of factors that stimulate or inhibit its transcriptional activity.…”

Section: Introductionmentioning

confidence: 99%