<i>Rb</i> and N-<i>ras</i> Function Together To Control Differentiation in the Mouse

Takahashi, Chiaki; Bronson, Roderick T.; Socolovsky, Merav; Contreras, Bernardo; Lee, Kwang Youl; Jacks, Tyler; Noda, Makoto; Kucherlapati, Raju; Ewen, Mark E.

doi:10.1128/mcb.23.15.5256-5268.2003

Cited by 45 publications

(55 citation statements)

References 66 publications

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“…Twenty-four hours after transfection, cells were trypsinized, mixed with 4 × 10 5 tumor cells, and cultured for 24 hours. Luciferase and β-galactosidase activities in cells were measured as described (23). β-Galactosidase activity was used to normalize luciferase activity in each transfection.…”

Section: Methodsmentioning

confidence: 99%

The β1-Integrin–Dependent Function of RECK in Physiologic and Tumor Angiogenesis

Miki

Shamma

Kitajima

et al. 2010

Molecular Cancer Research

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Vascular endothelial cells produce considerable amounts of matrix metalloproteinases (MMP), including MMP-2, MMP-9, and membrane type 1 (MT1)-MMP. However, little is known about the regulatory mechanisms of these protease activities exhibited during vascular development. A glycosylphosphatidylinositol-anchored glycoprotein, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), has been shown to attenuate MMP-2 maturation by directly interacting with MT1-MMP. Here, we show that an angiogenic factor angiopoietin-1 induces RECK expression in human umbilical vein endothelial cells (HUVEC), and RECK depletion in these cells results in defective vascular tube formation and cellular senescence. We further observed that RECK depletion downregulates β1-integrin activation, which was associated with decreased autophosphorylation of focal adhesion kinase and increased expression of a cyclin-dependent kinase inhibitor p21 CIP1 . In agreement, significant downregulation of β1-integrin activity was observed in vascular endothelial cells in Reck−/− mouse embryos. In HUVECs, specific inhibition of MMP-2 significantly antagonized the effect of RECK depletion on β1-integrin signaling, cell proliferation, and tube elongation. Furthermore, we observed that hypervascular tumor-derived cell lines can induce high RECK expression in convoluted vascular endothelial cells, and this in turn supports tumor growth. Targeting RECK specifically in tumor-associated vascular endothelial cells resulted in tumor regression. Therefore, we propose that RECK in tumor vascular endothelial cells can be an interesting target of cancer treatment via abortion of tumor angiogenesis.

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Section: Methodsmentioning

confidence: 99%

The β1-Integrin–Dependent Function of RECK in Physiologic and Tumor Angiogenesis

Miki

Shamma

Kitajima

et al. 2010

Molecular Cancer Research

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“…Conditional knock-out studies have suggested that Rb may have a role in regulating differentiation and migration (Takahashi et al, 2003;Ferguson et al, 2005;Chen et al, 2007;; however, the underlying mechanisms remain unknown. Clearly, indirect cross talk between the cell cycle machinery and differentiation pathways is essential to prevent premature differentiation of proliferating progenitors while promoting differentiation as cell division ceases.…”

Section: Introductionmentioning

confidence: 99%

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Ghanem¹,

Andrusiak²,

Svoboda³

et al. 2012

Journal of Neuroscience

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During brain morphogenesis, the mechanisms through which the cell cycle machinery integrates with differentiation signals remain elusive. Here we show that the Rb/E2F pathway regulates key aspects of differentiation and migration through direct control of the Dlx1 and Dlx2 homeodomain proteins, required for interneuron specification. Rb deficiency results in a dramatic reduction of Dlx1 and Dlx2 gene expression manifested by loss of interneuron subtypes and severe migration defects in the mouse brain. The Rb/E2F pathway modulates Dlx1/Dlx2 regulation through direct interaction with a Dlx forebrain-specific enhancer, I12b, and the Dlx1/Dlx2 proximal promoter regions, through repressor E2F sites both in vitro and in vivo. In the absence of Rb, we demonstrate that repressor E2Fs inhibit Dlx transcription at the Dlx1/Dlx2 promoters and Dlx1/2-I12b enhancer to suppress differentiation. Our findings support a model whereby the cell cycle machinery not only controls cell division but also modulates neuronal differentiation and migration through direct regulation of the Dlx1/Dlx2 bigene cluster during embryonic development.

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“…These phenotypes include alterations in cell differentiation, cell cycle control, and elevated apoptosis. Because the changes in tissue morphology in Rb mutant animals are often quite complex, involving both cellautonomous and nonautonomous changes (45,59,60,68), explaining why the inactivation of pRB causes these specific phenotypes is often a formidable challenge (reviewed in references 13 and 62).…”

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confidence: 99%

A Gradient of Epidermal Growth Factor Receptor Signaling Determines the Sensitivity of rbf1 Mutant Cells to E2F-Dependent Apoptosis

Moon

Stefano

Dyson

2006

Molecular and Cellular Biology

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The inactivation of retinoblastoma (Rb) family members sensitizes cells to apoptosis. This cell death affects the development of mutant animals and also provides a critical constraint to the malignant potential of Rb mutant tumor cells. The extent of apoptosis caused by the inactivation of Rb is highly cell type and tissue specific, but the underlying reasons for this variation are poorly understood. Here, we characterize a specific time and place during Drosophila melanogaster development where rbf1 mutant cells are exquisitely sensitive to apoptosis. During the third larval instar, many rbf1 mutant cells undergo E2F-dependent cell death in the morphogenetic furrow. Surprisingly, this pattern of apoptosis is not caused by inappropriate cell cycle progression but instead involves the action of Argos, a secreted protein that negatively regulates Drosophila epidermal growth factor receptor (EGFR [DER]) activity. Apoptosis of rbf1 mutant cells is suppressed by the activation of DER, ras, or raf or by the inactivation of argos, sprouty, or gap1, and inhibition of DER strongly enhances apoptosis in rbf1 mutant discs. We show that RBF1 and a DER/ras/raf signaling pathway cooperate in vivo to suppress E2F-dependent apoptosis and that the loss of RBF1 alters a normal program of cell death that is controlled by Argos and DER. These results demonstrate that a gradient of DER/ras/raf signaling that occurs naturally during development provides the contextual signals that determine when and where the inactivation of rbf1 results in dE2F1-dependent apoptosis.

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Rb and N-ras Function Together To Control Differentiation in the Mouse

Cited by 45 publications

References 66 publications

The β1-Integrin–Dependent Function of RECK in Physiologic and Tumor Angiogenesis

The β1-Integrin–Dependent Function of RECK in Physiologic and Tumor Angiogenesis

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

A Gradient of Epidermal Growth Factor Receptor Signaling Determines the Sensitivity of rbf1 Mutant Cells to E2F-Dependent Apoptosis

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