c‐jun‐NH2JNK mediates invasive potential and EGFR activation by regulating the expression of HB‐EGF in a urokinase‐stimulated pathway

Cáceres, Mónica; Tobar, Nicolás; Guerrero, Julien; Ph, Smith; Martı́nez, Jorge

doi:10.1002/jcb.21469

Cited by 12 publications

(10 citation statements)

References 23 publications

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“…In addition, the enhanced cell migration/invasion ability due to GRB7 expression was also abrogated by the JNK inhibitor SP600125. Our findings are consistent with previous studies that the increased phosphorylated ERK promotes cell proliferation and the elevated phosphorylated JNK enhances cell migration (29)(30)(31)(32)(33). These results further confer the molecular basis of differential functions between GRB7 and GRB7v.…”

Section: Discussionsupporting

confidence: 93%

Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis

Wang

Chan

Liu

et al. 2010

Clinical Cancer Research

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Purpose: Aberrant overexpression of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v has been found in numerous human cancers. The goal of this study was to characterize the functions of GRB7 and GRB7v in the ovarian carcinogenesis and to investigate the differential roles of GRB7 and GRB7v in the modulation of signaling pathways.Experimental Design: Quantitative reverse transcription-PCR, Western blot, and immunohistochemical analyses were used to evaluate the levels of GRB7 and GRB7v. The cellular localization, functions, and signaling pathways regulated by GRB7 and GRB7v were investigated by enforced expression of GRB7 and GRB7v.Results: Quantitative reverse transcription-PCR and Western blot analyses showed that GRB7 and GRB7v were frequently upregulated in ovarian cancer samples. The overexpressed GRB7 (P = 0.009) and GRB7v (P = 0.017) were significantly correlated with high-grade ovarian cancer. Immunohistochemical analysis on ovarian cancer tissue array confirmed that the upregulated GRB7 was significantly correlated with high-grade ovarian cancer (P = 0.001). Confocal microscopy analysis showed that GRB7 and GRB7v predominately localized in cytoplasm of ovarian cancer cells, consistent with their roles as signaling adaptors. Enforced expression of GRB7 promoted cell proliferation, migration, and invasion, whereas GRB7v only increased cell proliferation and anchorage-independent growth ability. With the treatment of specific kinase inhibitors, we showed that both GRB7 and GRB7v promoted cell proliferation through activating extracellular signal-regulated kinase signaling, whereas GRB7 enhanced cell migration/invasion by activating c-Jun NH 2 terminal kinase signaling.Conclusions: Our studies implicate that the overexpressed GRB7 and GRB7v are associated with highgrade tumors and exert distinct tumorigenic functions through regulating different signaling pathways in ovarian cancer cells. Clin Cancer Res; 16(9); 2529-39. ©2010 AACR.Ovarian cancer is one of the most deadly malignancies in women (1). Approximately 70% of ovarian cancer cases are diagnosed at the advanced stage, and the mortality rate has remained high for decades (2). It is widely accepted that genetic variations act in concert with other factors, such as hormonal and environmental factors, to potentiate the risk of ovarian cancer. However, the knowledge on the molecular basis of ovarian cancer development remains poor (3). Undoubtedly, a better understanding of the molecular pathogenesis of ovarian cancer may assist the development of novel therapeutic interventions for this disease.Tyrosine kinase signaling pathways are the major regulators of cell growth, cell division, and motility. The aberrant activation of these pathways attributes to the development of many human cancers (4, 5). The human growth factor receptor-bound protein 7 (GRB7) is a member of GRB7 adaptor protein family, which also includes GRB10 and GRB14, and acts as an adaptor bridging the growth factor receptor kinase proteins and their downstream ...

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Section: Discussionsupporting

confidence: 93%

Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis

Wang

Chan

Liu

et al. 2010

Clinical Cancer Research

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“…Highly elevated PLAUR transcript levels are also detected after cholesterol depletion (Figure 1). The urokinase system PLAU/PLAUR is mainly known for its fibrinolytic function during tissue remodeling; however, PLAUR is also involved in cell adhesion, migration, and signaling (Ragno, 2006;Caceres et al, 2008). Further investigations of this urokinase system represent promising areas of research because cholesterol biosynthesis is increased not only by PLAU binding to its receptor (Fuhrman et al, 2007) but also because PLAU secretion and increased PLAUR expression are induced as a response to cholesterol depletion.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling after Lipid Raft Disruption in Keratinocytes Identifies Critical Mediators of Atopic Dermatitis Pathways

Mathay

St.Pierre

Pittelkow

et al. 2011

Journal of Investigative Dermatology

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Lipid rafts are cholesterol-rich cell signaling platforms, and their physiological role can be explored by cholesterol depletion. To characterize transcriptional changes ongoing after lipid raft disruption in epidermal keratinocytes, a cell type that synthesizes its cholesterol in situ, we performed whole-genome expression profiling. Microarray results show that over 3,000 genes are differentially regulated. In particular, IL-8, urokinase-like plasminogen activator receptor, and metalloproteinases are highly upregulated after cholesterol extraction. Quantitative reverse transcriptase PCR validation and protein release measurements demonstrate the physiological relevance of microarray data. Major enriched terms and functions, determined by Ingenuity Pathways Analysis, identify cholesterol biosynthesis as a major function, illustrating the specificity of keratinocyte response toward cholesterol depletion. Moreover, the inflammatory skin disorder atopic dermatitis (AD) is identified as the disease most closely associated with the profile of lipid raft-disrupted keratinocytes. This finding is confirmed in skin of AD patients, in whom transcript levels of major lipid raft target genes are similarly regulated in lesional atopic skin, compared with non-lesional and normal skin. Thus, lipid raft disruption evokes typical features of AD, thereby suggesting that lipid raft organization and signaling could be perturbed in atopic keratinocytes.

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“…Total RNA was isolated using Trizol (Gibco BRL) from appropriately stimulated cells, and genomic DNA was eliminated using RQ1‐RNase‐free DNase (Promega, Madison, WI, USA). cDNA was synthesized for 1 h (42°C) with Moloney murine leukemia virus reverse transcriptase (Promega) using oligo dT (Gibco BRL), and RT‐PCR analyses were carried out as described previously (28). Primer sequences were as follows: urokinase‐type plasminogen activator forward 5′‐GCA GGA ACC CAG ACA ACC G‐3′/urokinase‐type plasminogen activator reverse 5′‐GAC CCA GGT AGA CGA TGT AG‐3′ (yielding an amplified PCR product of 357 bp).…”

Section: Methodsmentioning

confidence: 99%

Triclosan inhibits tumor necrosis factor‐α‐stimulated urokinase production in human gingival fibroblasts

Arancibia

Cáceres

Martı́nez

et al. 2009

J of Periodontal Research

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c‐jun‐NH2JNK mediates invasive potential and EGFR activation by regulating the expression of HB‐EGF in a urokinase‐stimulated pathway

Cited by 12 publications

References 23 publications

Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis

Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis

Transcriptional Profiling after Lipid Raft Disruption in Keratinocytes Identifies Critical Mediators of Atopic Dermatitis Pathways

Triclosan inhibits tumor necrosis factor‐α‐stimulated urokinase production in human gingival fibroblasts

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