Repression of transforming growth factor beta signaling by epidermal growth factor, Ras and interferon gamma.
Item
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Title
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Repression of transforming growth factor beta signaling by epidermal growth factor, Ras and interferon gamma.
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Identifier
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AAI9997087
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identifier
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9997087
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Creator
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Doody, Jacqueline.
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Contributor
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Adviser: David Foster
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Date
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2001
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Cell
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Abstract
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The transforming growth factor beta (TGFbeta) family of ligands is comprised of numerous members involved in a wide range of cellular processes including cell proliferation, growth inhibition, differentiation, wound healing and apoptosis. These processes are mediated by the action of ligand binding to serine/threonine kinase receptors that phosphorylate a signaling molecule, Smad, necessary for nuclear transmission of (TGFbeta) and the related bone morphogenetic protein (BMP) signaling factor. Smad proteins bind to DNA directly or in conjunction with partner transcription factors to activate (TGFbeta) and BMP-inducible genes. This thesis makes the determination that phosphorylation of Smads at their carboxy-terminal serines is responsible for Smad nuclear translocation and transcription activation since mutation of these serines abolishes these Smad activation events. Furthermore, phosphorylation of Smads by the serine/threonine kinase receptor is direct since the purified receptor can phosphorylate Smad in vitro. Smads therefore provide a link between receptor kinases and the nucleus.;This thesis additionally focuses on (TGFbeta) and BMP-antagonistic signaling pathways and their repression of (TGFbeta) signaling by targeting Smad proteins. Epidermal growth factor (EGF) and other growth factors necessary for proliferation activate the signaling molecule, Erk, responsible for phosphorylating Smad at several serines in the middle of the Smad molecule. Phosphorylation of Smad by Erk results in a decrease of nuclear accumulation of Smad and thus inhibits activation of (TGFbeta) and BMP-responsive genes. Moreover, overexpression of Ras, another signaling molecule for EGF, inhibits (TGFbeta) signaling. Therefore one mechanism which may contribute to transformation of cells by oncogenic Ras is to prevent (TGFbeta) growth inhibition by limiting Smad nuclear accumulation. Crosstalk between interferon gamma (IFNgamma) and (TGFbeta) also involves inhibitory phosphorylation of Smad although this is not the principal mechanism of repression. (IFNgamma) induces the expression of Smad7, an antagonist of the TGFbeta-inducible signaling molecule, Smad3. Smad7 inhibits binding of Smad3 to the (TGFbeta) receptors preventing activation of Smad3 in response to (TGFbeta) These results suggest that (IFNgamma) and EGF use different mechanisms to reach the same goal: inhibition of (TGFbeta) signaling.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
