The p53 orchestra: Mdm2 and Mdmx set the tone

Wade, Mark; Wang, Yunyuan V.; Wahl, Geoffrey M.

doi:10.1016/j.tcb.2010.01.009

Cited by 380 publications

(435 citation statements)

References 129 publications

(127 reference statements)

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“…It can occur via many mechanisms, including genetic alterations, such as gene mutations or deletions, epigenetic events that lead to gene silencing, and/or proteasomal degradation, as shown, for example, for p53, PTEN, and NF1 (56,87,89). Our findings indicate that ubiquitin-proteasome-mediated degradation of Dok-1 is a key mechanism by which OTKs trigger Dok-1 "inactivation."…”

Section: Discussionmentioning

confidence: 55%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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Section: Discussionmentioning

confidence: 55%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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“…Although loss of p53 function causes tumor susceptibility, hyperactivation of p53 is lethal; therefore, p53 activity must be severely regulated for normal tissue homeostasis maintenance (Wade et al, 2010). MDM2 is a crucial negative regulator of p53, that promote its degradation, as disclosed by models in which deletion of MDM2 gene is lethal in a p53-dependent manner (Marine et al, 2006;Ren et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Effects of p53 Codon 72 and MDM2 SNP309 Polymorphisms on Gastric Cancer Risk among the Iranian Population

Moradi

Salehi²,

Aminian³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. Materials and Methods: A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR (AS-PCR). Results: There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). Conclusions: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.

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“…90 A critical negative modulator of p53 is MDM2 and its homolog MDMX. 91 Despite bearing a RING domain, MDMX exhibits no intrinsic E3 activity. Rather, MDMX drives p53 degradation by forming a heterodimer with MDM2, the bona fide RING E3 ligase, which is mediated by a homotypic RING-RING interaction.…”

Section: Apoptosis Regulation By the Ubiquitin Systemmentioning

confidence: 99%

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

Chai

Liu

2016

Cell Mol Immunol

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The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.

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The p53 orchestra: Mdm2 and Mdmx set the tone

Cited by 380 publications

References 129 publications

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Effects of p53 Codon 72 and MDM2 SNP309 Polymorphisms on Gastric Cancer Risk among the Iranian Population

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

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