The MDM2 gene family

Abstract

MDM2 is an oncoprotein that blocks p53 tumor suppressor-mediated transcriptional transactivation, escorts p53 from the cell nucleus to the cytoplasm, and polyubiquitylates p53. Polyubiquitylated p53 is rapidly degraded in the cytoplasm by the 26S proteasome. MDM2 is abnormally upregulated in several types of cancers, especially those of mesenchymal origin. MDM4 is a homolog of MDM2 that also inhibits p53 by blocking p53-mediated transactivation. MDM4 is required for MDM2-mediated polyubiquitylation of p53 and is abnormally upregulated in several cancer types. MDM2 and MDM4 genes have been detected in all vertebrates to date and only a single gene homolog, named MDM, has been detected in some invertebrates. MDM2, MDM4, and MDM have similar gene structures, suggesting that MDM2 and MDM4 arose through a duplication event more than 440 million years ago. All members of this small MDM2 gene family contain a single really interesting new gene (RING) domain (with the possible exception of lancelet MDM) which places them in the RING-domain superfamily. Similar to MDM2, the vast majority of proteins with RING domains are E3 ubiquitin ligases. Other RING domain E3 ubiquitin ligases that target p53 are COP1, Pirh2, and MSL2. In this report, we present evidence that COP1, Pirh2, and MSL2 evolved independently of MDM2 and MDM4. We also show, through structure homology models of invertebrate MDM RING domains, that MDM2 is more evolutionarily conserved than MDM4.

MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke

“…MDM2 is an oncoprotein that blocks p53 tumor suppressormediated transcriptional transactivation [10]. A deeper understanding of MDM2 regulation will help us to develop new and more effective strategies for ischemic stroke treatment that target MDM2 and activate p53 signaling in cells, owing to the critical role MDM2 plays in human disease.…”

Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations

“…Concurrent MDM2amp was the most common amplification identified in our series of METex14 cases, and it has been identified as an oncogenic event in diverse tumor types acting through negative regulation of p53 function through ubiquination. 27,28 CBL is the ubiquitin ligase implicated as being primarily responsible for ubiquitination of MET due to the presence of a tyrosine kinase binding domain. 29 While METex14 protein lacks a tyrosine kinase binding domain, it is unknown whether MDM2amp is a compensatory mechanism to increase ubiquitination of MET through a different portion of MET protein or an event independent of METex14 alterations.…”

Validation of a Multiplexed Gene Signature Assay for Diagnosis of Canine Cancers from Formalin‐Fixed Paraffin‐Embedded Tissues

“…Rezaie et al reported MDM2 protein expression and limited polymorphisms in a small sample of canine tumors including mammary carcinoma and lymphoma,23 and we observed protein expression in melanomas by IHC. MDM2 is the central regulator of p53 by mediating its ubiquitination and nuclear and cytoplasmic degradation 24. Thus, by its action MDM2 suppresses p53 and overexpression of MDM2 is linked to an alternative pathway for wild‐type p53‐mediated oncogenesis.…”

“…MDM2 is the central regulator of p53 by mediating its ubiquitination and nuclear and cytoplasmic degradation. 24 Thus, by its action MDM2 suppresses p53 and overexpression of MDM2 is linked to an alternative pathway for wild-type p53-mediated oncogenesis. E2F1, a negative regulator of the tumor suppressor retinoblastoma gene, is linked to MDM2-p53 pathway in oncogenesis.…”