The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach

Nakagawa, Hiroshi; Wang, Yichen; Zukerberg, Lawrence; Odze, Robert D.; Togawa, Kazumi; May, Gerhard; Wilson, Joanna B.; Rustgi, Anil K.

doi:10.1038/sj.onc.1200937

Cited by 123 publications

(97 citation statements)

References 18 publications

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“…Amplification or mutation of the cyclin D1 gene has not been reported in GC, although elevated cyclin D1 expression has been observed in ≈50% of GC cases (37). In GC, several factors are reportedly involved in cyclin D1 overexpression, including the RAF/MEK/ERK pathways (38), abrogation of TGF-β signaling (39), gastrin (40,41), Epstein-Barr virus (42), and H. pylori (43). However, the precise mechanism that regulates cyclin D1 expression in GC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. JNK | c-JunG astric cancer (GC) is a common cancer worldwide, associated with a high mortality despite its declining incidence in recent decades. Smoking, salted or smoked foods, and Helicobacter pylori appear to be major environmental inducers of GC (1-3). Although the role of H. pylori in causing mucosal effects has been investigated, which molecular signal(s) initiate the program of irreversible transformation remain unclear, and thus molecular targeting therapies for GC have not been well established.Mitogen-activated protein kinase (MAPK) pathways are important for the development of gastric tumorigenesis (4). Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPK kinase kinase (MAP3K), activated by various stress stimuli, including reactive oxygen species (ROS), TNF-α, and LPS (5-7). ASK1 activates the JNK and p38 signaling pathways and is required for both oxidative stress and cytokine-induced apoptosis (5). Furthermore, ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response (5,7,8) and has been reported to be involved in the pathogenesis of various human diseases, including neurodegenerative (9), cardiovascular (10), and inflammatory diseases (11,12). Additionally, ASK1 has been shown to participate in both colon (12) and skin (13) tumorigenesis through the regulation of inflammation and apoptosis. However, no reported study has demonstrated a role for ASK1 in gastric tumorigenesis.In this study, we examined the role of ASK1 in gastric tumorigenesis using both human GC samples and ASK1-deficient (ASK1 −/− ) mice. We demonstrated that ASK1 is important for gastric tumorigenesis through the regulation of cyclin D1 e...

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Section: Discussionmentioning

confidence: 99%

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The EGFR transgene is expressed in a tissue-specific fashion with targeting to the tongue, esophagus, and forestomach (10). The EGFR transgenic mice and age-matched wildtype mice were sacrificed at age 6 months for histology and immunohistochemistry.…”

Section: Generation Of Egfr Transgenic Mice and Cell Lines Of Mouse Ementioning

confidence: 99%

Epidermal Growth Factor Receptor Mediates Increased Cell Proliferation, Migration, and Aggregation in Esophageal Keratinocytes in Vitro and in Vivo

Andl¹,

Mizushima²,

Nakagawa³

et al. 2003

Journal of Biological Chemistry

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227

225

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Epidermal growth factor receptor (EGFR) overexpression is observed in a number of malignancies, especially those of esophageal squamous cell origin. However, little is known about the biological functions of EGFR in primary esophageal squamous epithelial cells. Using newly established primary human esophageal squamous epithelial cells as a platform, we overexpressed EGFR through retroviral transduction and established novel threedimensional organotypic cultures. Additionally, EGFR was targeted in a cell type-and tissue-specific fashion to the esophageal epithelium in transgenic mice. EGFR overexpression in primary esophageal keratinocytes resulted in the biochemical activation of Akt and STAT pathways and induced enhanced cell migration and cell aggregation. When established in organotypic culture, EGFR-overexpressing cells had evidence of epithelial cell hyperproliferation and hyperplasia. These effects were also observed in EGFR-overexpressing transgenic mice and the esophageal cell lines established thereof. In particular, EGFR-induced effects upon aggregation appear to be mediated through the relocalization of p120 from the cytoplasm to the membrane and increased interaction with E-cadherin. EGFR modulates cell migration through the up-regulation of matrix metalloproteinase 1. Taken together, the functional effects of EGFR overexpression help to explain its role in the initiating steps of esophageal squamous carcinogenesis. Epidermal growth factor receptor (EGFR)1 is a transmembrane protein receptor with tyrosine kinase activity that triggers numerous signaling pathways (1-3). Activation of the EGFR tyrosine kinase results in the generation of a number of intracellular signals, which culminate in not only cell proliferation but also other processes that are crucial to cancer progression, including angiogenesis, metastatic spread, and the inhibition of apoptosis. These events are mediated through various downstream targets of EGFR (e.g. the serine/threonine kinase Raf and mitogen-activated protein/extracellular signalregulated kinase 1/2). In addition, Ras activation by EGFR is required for a vast array of cellular functions, foremost of which is the regulation of cellular proliferation. Activation of EGFR also results in the activation of the lipid kinase phosphatidylinositol 3-kinase, generating the second messenger phosphatidylinositol 3,4,5-trisphosphate, which in turn activates Akt. We have previously demonstrated that there is differential activation of the Akt isoforms by EGFR in esophageal cancer cells (4). Apart from the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, EGFR also activates other pathways such as phospholipase-C and its downstream protein kinase cascades, small GTPases such as Rho, and multiple signal transducer and activator of transcription (STAT) isoforms.EGFR activation is not only important in normal cellular processes, but it is frequently altered or overexpressed in many malignancies, especially those of squamous cell origin. Mechanisms that mediate E...

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“…Nakagawa et al used an Epstein-Barr virus (EBV) ED-L2 promoter in a construct to target human cyclin D1 in transgenic mice. 4 They observed the expression of the cyclin D1 transgene in oral and esophageal epithelia and a phenotype that showed mild dysplasia by 6-12 months, with progression to moderatesevere dysplasia by 15-16 months. Overexpression of PCNA and abnormalities in cyclin-dependent kinase-4, EGFR and p53 during early HNSCC carcinogenesis were also demonstrated, 5 but no evidence of cancer was noted.…”

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confidence: 99%

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations part B. Transgenic mouse models

Thomas

Smith

2006

Intl Journal of Cancer

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Experimental multistage carcinogenesis involves three broad sequential steps: tumor initiation, tumor promotion and tumor progression, and appear to be similar to human carcinogenesis. However, we expect that these processes in humans will be more complex and may not occur in a predictable order. The net result of a number of events such as activation of oncogenes, inactivation of tumor suppressor genes and expression of apoptosis-regulating genes may likely contribute to the accumulation of multiple genetic alterations, leading to tumor formation. In addition, humans are exposed to multiple mutagenic agents that may act at the same time on tumor initiation, promotion or progression. The classical animal models fall short of providing important information concerning carcinogen-host and tumor-host interactions.The development of animals with overexpression or inactivation of carcinogenesis-related genes has expedited studies on carcinogenesis and its prevention and treatment. These transgenic animals provide a powerful model to explore mechanisms of gene expression as well as the regulation of cellular and physiologic processes involved in initiation, promotion and progression of cancer. With this technology, targeted expression of a protein can be achieved in a controlled fashion by expressing the corresponding gene in vivo ectopically, ubiquitously or in a tissue-specific manner, using its own promoter. These newer models may provide more precise control over gene expression at various stages of development through activation of mutant alleles at precise points in the developmental process using conditional Cre-Lox and tetracycline-inducible technology. The Cre-LoxP and the tetracycline (Tet)-inducible systems are useful methods of conditional gene expression that allow spatial (celltype-specific) and temporal (inducer-dependent) control. The Cre-LoxP system, which has been widely used for gene manipulation in animal models, uses P1 phage Cre-recombinase to catalyze the excision of DNA located between flanking loxP sites for conditional gene inactivation. Tetracycline-controlled gene expression relies on two components: (i) a tetracycline-responsive transactivator (tTA) that is, a fusion of E. Coli tet repressor to the transactivation domain of VP16 protein of herpes simplex virus, and (ii) a tTA-dependent promoter consisting of a minimal RNA polymerase II promoter fused to tet operator sequences. By using a reverse tTA, which becomes transcriptionally active only when bound to tetracycline or its derivatives, expression of a target gene can be induced by administration of tetracycline or doxycycline. [1][2][3] In recent years, several transgenic mouse models with overexpression or inactivation of cancer-related genes using the CreLoxP technology have been used to study the initiation, development and metastasis of epidermal/cutaneous squamous cell carcinoma (SCC). However, the use of these animal model systems for the study of head and neck squamous cell carcinoma (HNSCC) is still in its infancy. Studies of s...

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The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach

Cited by 123 publications

References 18 publications

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Epidermal Growth Factor Receptor Mediates Increased Cell Proliferation, Migration, and Aggregation in Esophageal Keratinocytes in Vitro and in Vivo

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations part B. Transgenic mouse models

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