Expression of NEDD‐1, a PTEN regulator, in gastric and colorectal carcinomas

Kim, Sung Soo; Yoo, Nam Jin; Jeong, Eun Goo; Kim, Min Sung; Lee, Sug Hyung

doi:10.1111/j.1600-0463.2008.00999.x

Cited by 56 publications

(48 citation statements)

References 16 publications

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“…Interestingly, as in previous studies with various cancer cells (30,49), we observed an inverse correlation between PTEN and NEDD4-1 protein levels upon zinc treatment in mouse brains (Fig. 7).…”

Section: Discussionsupporting

confidence: 71%

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Kwak

Wang

Pan

et al. 2010

Journal of Biological Chemistry

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The contribution of zinc-mediated neuronal death in the process of both acute and chronic neurodegeneration has been increasingly appreciated. Phosphatase and tensin homologue, deleted on chromosome 10 (PTEN), the major tumor suppressor and key regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, plays a critical role in neuronal death in response to various insults. NEDD4-1-mediated PTEN ubiquitination and subsequent degradation via the ubiquitin proteosomal system have recently been demonstrated to be the important regulatory mechanism for PTEN in several cancer types. We now demonstrate that PTEN is also the key mediator of the PI3K/Akt pathway in the neuronal response to zinc insult. We used primary cortical neurons and neuroblastoma N2a cells to show that zinc treatment results in a reduction of the PTEN protein level in parallel with increased NEDD4-1 gene/protein expression. The reduced PTEN level is associated with an activated PI3K pathway as determined by elevated phosphorylation of both Akt and GSK-3 as well as by the attenuating effect of a specific PI3K inhibitor (wortmannin). The reduction of PTEN can be attributed to increased protein degradation via the ubiquitin proteosomal system, as we show NEDD4-1 to be the major E3 ligase responsible for PTEN ubiquitination in neurons. Moreover, PTEN and NEDD4-1 appear to be able to counter-regulate each other to mediate the neuronal response to zinc. This reciprocal regulation requires the PI3K signaling pathway, suggesting a feedback loop mechanism. This study demonstrates that NEDD4-1-mediated PTEN ubiquitination is crucial in the regulation of PI3K/Akt signaling by PTEN during the neuronal response to zinc, which may represent a common mechanism in neurodegeneration.Zinc is increasingly recognized as an important molecule that plays both physiological and pathological roles in a variety of biological processes. The role of zinc in the central nervous system has also been discovered over the past 2 decades, as a neurotransmitter in modulating synaptic plasticity (1, 2). Although zinc is selectively stored in the pre-synaptic vesicles of a specific type of neuron, sequestered or tightly bound to cellular compartments, it can be rapidly released in response to extracellular signals. The same neurons also secrete glutamate and are the so-called "gluzinergic" neurons found primarily in the mammalian cerebral cortex. Neurons store up to 300 M free zinc in their termini (3) and release it through several types of cation channels (e.g. N-methyl-D-aspartic acid receptors) when they are depolarized, reaching high concentrations that are known to cause acute neuronal death. Together with glutamate, zinc mediates excitotoxicity, as manifested in acute brain injuries, ischemia, and seizures (4, 5). Zinc is also implicated in chronic neurodegenerative diseases such as Alzheimer disease via direct chelation with the amyloid precursor protein, thereby modulating its processing and generating oxidative stress (6).In cortical cell cultures, 100 M zinc, with ...

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Section: Discussionsupporting

confidence: 71%

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Kwak

Wang

Pan

et al. 2010

Journal of Biological Chemistry

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“…To our knowledge this is the first thorough study of NEDD4-1 expression in human cancer with a significant correlation with PTEN status: NEDD4-1 overexpression has been reported in limited cohorts of patients with urinary bladder (mRNA) and gastrointestinal (protein) cancers. 24,35 The TMA immunostaining studies reported in this article demonstrated that most NSCLC overexpress NEDD4-1 compared with normal lung epithelium, implying that the acquisition of NEDD4-1 expression might represent an oncogenic event during cancer development in the lung. The observation that there is no significant difference in NEDD4-1 levels with respect to histological subtypes, grade, stage, or metastasis, suggests that enhanced NEDD4-1 expression might occur at an early stage of the tumorigenic process.…”

Section: Discussionmentioning

confidence: 99%

“…33,34 The antibody used in immunostaining of TMAs for NEDD4-1 (number 07-049, Upstate Biotechnology, Lake Placid, NY) had been developed by immunizing rabbit with a synthetic peptide of the NEDD4-1WW domain and its specificity was described in a previous study on colon and gastric cancer. 35 The specificity of the antibodies used in our study was assessed by three control experiments: absence of consistent immunostaining of cells when the anti-NEDD4-1 or anti-PTEN antibodies were replaced with normal rabbit serum at the same dilution; progressive reduction of signal intensity as dilution of the antibody was increased; and abrogation of signal after pre-incubation with the immunizing peptide.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Amodio

Scrima²,

Palaia

et al. 2010

The American Journal of Pathology

127

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Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n ‫؍‬ 98; P < 0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).

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“…The Nedd4-IRS-2 binding may represent a novel drug target at least in prostate cancer. Accumulating evidence suggests that Nedd4 is overexpressed in various cancers and functions as a tumour-promoting factor [17][18][19][20][21] . It is important to investigate the contribution of the Nedd4-IRS-2 complex to the development of various cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Nedd4 knockout mice show fetal growth retardation and perinatal lethality 16 , indicating a crucial role for Nedd4 in embryonic growth. Nedd4 is overexpressed in several types of cancers and functions as an oncogenic protein [17][18][19][20][21] . We provide multiple lines of evidence, suggesting that Nedd4 conjugates monoubiquitin to IRS-2 and recruits IRS-2 to the plasma membrane, thereby enhancing IRS-2 tyrosine phosphorylation by IGF-IR and IGF-I mitogenic activity.…”

mentioning

confidence: 99%

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

et al. 2015

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Expression of NEDD‐1, a PTEN regulator, in gastric and colorectal carcinomas

Cited by 56 publications

References 16 publications

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

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