Expression of the <i>neu</i> oncogene under the transcriptional control of the myelin basic protein gene in transgenic mice: Generation of transformed glial cells

Hayes, Carol; Kelly, Douglas G.; Murayama, Shigeo; Komiyama, Atsushi; Suzuki, Kinuko; Popko, Brian

doi:10.1002/jnr.490310123

Cited by 43 publications

(30 citation statements)

References 65 publications

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“…Thus, it seems that dysregulation of specific molecular pathways can influence tumor phenotype independent of the cell of origin. Furthermore, transgenic modeling of gliomagenesis directed towards the formation of oligodendrogliomas has resulted in astrocytomas (30). Conversely, transgenic strategies directed towards the formation of astrocytoma have generated oligodendrogliomas (31), supporting the view that astrocytes and oligodendrocytes have a common origin, their bidirectional movement along differentiating pathways subject to influence by a host of factors.…”

Section: Gliomas and Their Cell(s) Of Originmentioning

confidence: 94%

Epidermal Growth Factor Receptor–Mediated Signal Transduction in the Development and Therapy of Gliomas

Nicholas

Lukas²,

Jafri

et al. 2006

Clinical Cancer Research

197

131

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The epidermal growth factor receptor (EGFR) and its ligands figure prominently in the biology of gliomas, the most common tumors of the central nervous system (CNS). Although their histologic classification seems to be straightforward, these tumors constitute a heterogeneous class of related neoplasms. They are associated with a variety of molecular abnormalities affecting signal transduction, transcription factors, apoptosis, angiogensesis, and the extracellular matrix. Under normal conditions, these same interacting factors drive CNS growth and development. We are now recognizing the diverse molecular genetic heterogeneity that underlies tumors classified histologically into three distinct grades. This recognition is leading to new therapeutic strategies targeted directly at specific molecular subtypes. In this article, we will review the role of EGFR and related molecular pathways in the genesis of the normal CNS and their relationship to glial tumorigenesis. We will discuss barriers to effective treatment as they relate to anatomic specialization of the CNS. We will also consider the ways in which specific EGFR alterations common to glioma reflect outcomes following treatment with targeted therapies, all with an eye towards applying this understanding to improved patient outcomes. Epidermal growth factor (EGF) was identified by embryologistStanley Cohen in the early 1960s and its receptor (EGFR) was identified a decade later (1, 2). During that time and in the decades that followed, a family of related factors and their receptors were identified. The complex intracellular effects that follow activation of these receptors were subsequently elaborated. Together, this would prove to be of critical importance in our understanding of both normal growth and development and neoplastic transformation. This review will focus on the role of these receptor-ligand interactions in primary brain tumor biology. We will briefly discuss their importance in the development of normal brain and the implication of those roles for tumorigenesis. Following a review of specific abnormalities in brain tumors, we will conclude with a summary of brain tumor therapies that include EGFR-mediated signaling in their rationale. Receptor-Ligand InteractionsThe EGFR was the first of the human EGF receptor (HER) family members to be discovered. The HER family proteins are members of the receptor tyrosine kinase (RTK) superfamily. The platelet-derived growth factor receptor (PDGFR), another RTK family member, is also important in brain tumor biology. The ligands for the HER family receptors are also diverse. They include the EGF family and the structurally related neuregulin family. Both are produced by many cell types, including neurons and glia. All of the ligands function via autocrine and/ or paracrine signaling. The EGF family includes EGF, transforming growth factor-a (TGF-a), heparin-binding EGF, amphiregulin, betacellulin, and epiregulin (3).The neuregulin (NRG) family consists of the protein products derived from the alternat...

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Section: Gliomas and Their Cell(s) Of Originmentioning

confidence: 94%

Epidermal Growth Factor Receptor–Mediated Signal Transduction in the Development and Therapy of Gliomas

Nicholas

Lukas²,

Jafri

et al. 2006

Clinical Cancer Research

197

131

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“…15 Under 1% FBS conditions, the cells display an oligodendrocyte-like morphology and express MBP and other myelin-specific proteins. Transduction of MOCH-1 cells by rAAV-MBP-GFP produced GFP protein as early as 24 h after infection as demonstrated by the natural GFP green fluorescence.…”

Section: Recombinant Aav Virusesmentioning

confidence: 99%

Gene transfer and expression in oligodendrocytes under the control of myelin basic protein transcriptional control region mediated by adeno-associated virus

et al. 1998

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In this study, a rAAV vector carrying a reporter gene,Infusion of approximately 6 × 10 9 particles (2 × 10 5 infec-'humanized' green fluorescent protein (GFP), linked to the tious units) of rAAV-MBP-GFP into mouse brains resulted transcriptional control region from the myelin basic protein in the GFP expression specifically in white matter. The (MBP) gene (a myelin-forming cell-specific gene) was con-GFP protein was detected 15 days later by immunostainstructed. Transduction of oligodendrocytes was carried out ing, specifically in the oligodendrocytes. No astrocytes both in vitro and in vivo. The GFP expression was detected were transduced. Our studies suggested that cell types for at least 3 weeks in both transduced oligodendrocyte cell other than neurons in the central nervous system can also line (MOCH-1 cells) and primary cultures of rat oligodendbe transduced by rAAV using a cell-type-specific transcriprocytes. Preferential GFP expression in oligodendrocytes tional control region or promoter. The MBP transcriptional was observed in the primary cultures. In contrast, transduccontrol region might be suitable for gene therapy and other tion with rAAV carrying the CMV promoter produced neurobiology studies requiring direct targeting to the myelistronger GFP fluorescence in various cell types, with the nating cells. majority of GFP-expressing cells being the astrocytes.

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“…Evidence that NRG-1 / erbB2 might contribute to the transformation of glial cells comes from studies that demonstrate NRG-1 can induce the de-differentiation and proliferation of cultured oligodendrocytes (Canoll et al, 1999) and from transgenic mice that express the activated neu (Hayes et al, 1992) oncogene under the control of the myelin basic protein promoter. These mice developed tumors that exhibited pathological features that resembled that of the most aggressive form of astrocytoma, the glioblastoma multiforme.…”

Section: Introductionmentioning

confidence: 99%

Neuregulin‐1 enhances survival of human astrocytic glioma cells

Ritch

Carroll

Sontheimer

2005

Glia

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Malignant astrocytic gliomas, referred to as astrocytomas, represent the most commonly diagnosed adult primary brain tumor. These tumors are characterized by unrelenting growth that is often resistant to chemotherapy and radiation therapy. Tumor expansion into the healthy surrounding brain tissue produces severe and often fatal consequences. In this study, we examine the potential for the neuregulin-1/erbB receptor signaling cascade to contribute to this process by modulating glioma cell growth. Using antibodies specific for the erbB receptors, we demonstrate the expression patterns for the erbB2, erbB3, and erbB4 receptors in human glioma biopsy samples. We then verify receptor expression in a panel of human glioma cell lines. Next, we investigate the status of the erbB2 and erbB3 receptors in the human glioma cell lines and find that they are constitutively tyrosine-phosphorylated and heterodimerized. Subsequently, we demonstrate that theses same cell lines express membrane bound and released forms of neuregulins, the erbB receptor ligands, suggesting a possible autocrine or paracrine signaling network. Furthermore, we show that exogenous activation of erbB2 and erbB3 receptors in U251 glioma cells by recombinant Nrg-1beta results in enhanced glioma cell growth under conditions of serum-deprivation. This enhancement is due to an increase in cell survival rather than an increase in cell proliferation and is dependent on the activation of erbB2 and phosphatidylinositol-3 kinase (PI3K). Moreover, Nrg-1beta activates an inhibitor of apoptosis, Akt, implying a possible role for this kinase in mediating Nrg-1beta effects in gliomas. This data suggests that glioma cells may use autocrine or paracrine neuregulin-1/erbB receptor signaling to enhance cell survival under conditions where growth would otherwise be limited.

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Expression of the neu oncogene under the transcriptional control of the myelin basic protein gene in transgenic mice: Generation of transformed glial cells

Cited by 43 publications

References 65 publications

Epidermal Growth Factor Receptor–Mediated Signal Transduction in the Development and Therapy of Gliomas

Epidermal Growth Factor Receptor–Mediated Signal Transduction in the Development and Therapy of Gliomas

Gene transfer and expression in oligodendrocytes under the control of myelin basic protein transcriptional control region mediated by adeno-associated virus

Neuregulin‐1 enhances survival of human astrocytic glioma cells

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