Mammalian Numb is a target protein of Mdm2, ubiquitin ligase

Yogosawa, Satomi; Miyauchi, Yasuhiro; Honda, Reiko; Tanaka, Hirofumi; Yasuda, Hideyo

doi:10.1016/s0006-291x(03)00282-1

Cited by 54 publications

(43 citation statements)

References 21 publications

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“…This result is of particular interest because of its relation to the p53 pathway. NUMB is known to bind to both TP53 and MDM2 separately and may potentially form a triplex with TP53 and MDM2, stabilizing and preventing TP53 from being degraded (33)(34)(35). Further experiments are required to determine whether the observed splicing event affects the binding of NUMB to TP53 and MDM2.…”

Section: Discussionmentioning

confidence: 99%

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Kusko

Tedrow

Pandit

et al. 2016

Am J Respir Crit Care Med

117

113

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Rationale: Despite shared environmental exposures, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease are usually studied in isolation, and the presence of shared molecular mechanisms is unknown.Objectives: We applied an integrative genomic approach to identify convergent transcriptomic pathways in emphysema and IPF.Methods: We defined the transcriptional repertoire of chronic obstructive pulmonary disease, IPF, or normal histology lungs using RNA-seq (n = 87).Measurements and Main Results: Genes increased in both emphysema and IPF relative to control were enriched for the p53/hypoxia pathway, a finding confirmed in an independent cohort using both gene expression arrays and the nCounter Analysis System (n = 193). Immunohistochemistry confirmed overexpression of HIF1A, MDM2, and NFKBIB members of this pathway in tissues from patients with emphysema or IPF. Using reads aligned across splice junctions, we determined that alternative splicing of p53/hypoxia pathway-associated molecules NUMB and PDGFA occurred more frequently in IPF or emphysema compared with control and validated these findings by quantitative polymerase chain reaction and the nCounter Analysis System on an independent sample set (n = 193). Finally, by integrating parallel microRNA and mRNA-Seq data on the same samples, we identified MIR96 as a key novel regulatory hub in the p53/hypoxia gene-expression network and confirmed that modulation of MIR96 in vitro recapitulates the disease-associated gene-expression network.Conclusions: Our results suggest convergent transcriptional regulatory hubs in diseases as varied phenotypically as chronic obstructive pulmonary disease and IPF and suggest that these hubs may represent shared key responses of the lung to environmental stresses.

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Section: Discussionmentioning

confidence: 99%

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Kusko

Tedrow

Pandit

et al. 2016

Am J Respir Crit Care Med

117

113

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“…Although MDM2 originally functions as an E3 ligase to degrade p53 (44 -46), MDM2 also targets other proteins, such as the androgen receptor (47) and Numb (a protein that plays an important role in specifying cell fate during development) (48,49), for ubiquitination and degradation. Because we observed an increase in the phosphorylation/activation of MDM2 despite its elevated degradation after treatment of cells with cycloheximide, we speculate the altered degradation or half-lives of the proteins that are substrates of MDM2, when protein biosynthesis is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Synthesis Alters Protein Degradation through Activation of Protein Kinase B (AKT)

Dai

Shi

Chen

et al. 2013

Journal of Biological Chemistry

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Background: Whether a change in protein biosynthesis modulates protein degradation is unknown. Results: Inhibition of protein biosynthesis induces activation of AKT (protein kinase B), leading to activation of E3 ubiquitin ligase and thus degradation of its substrate proteins. Conclusion: Protein degradation is regulated by protein biosynthesis. Significance: This study reveals a novel regulation of protein degradation.

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“…85 Mdm2 had been shown to bind NUMB and promote its ubiquitylation and degradation. 86,87 The NUMB-Mdm2 physical and functional interaction has more recently been revisited. The physical interaction has been confirmed at endogenous levels of protein expression.…”

Section: Regulation Of Mdm2-mediated P53 Ubiquitylationmentioning

confidence: 99%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

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The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

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Mammalian Numb is a target protein of Mdm2, ubiquitin ligase

Cited by 54 publications

References 21 publications

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Inhibition of Protein Synthesis Alters Protein Degradation through Activation of Protein Kinase B (AKT)

Mdm2-mediated ubiquitylation: p53 and beyond

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