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    Gene regulation downstream of glycogen synthase kinase-3 in neonatal rat ventricular myocytes and T98G cells

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    Date Issued
    2012
    Author(s)
    Brennan, James F.
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    Embargoed until:
    Indefinite
    Permanent Link
    https://hdl.handle.net/2144/12294
    Abstract
    Glycogen synthase kinase-3 (GSK-3) is a regulatory kinase involved in many important mammalian cell functions. The PI 3-kinase/Akt pathway, which is a major regulator of cell growth and survival in proliferating cells, directly inhibits GSK-3. Inhibition of the PI 3-kinase pathway induces expression of cell cycle arrest and pro-apoptotic genes. Some ofthese genes are induced downstream ofGSK-3 signaling. In this study we show that some genes induced following PI 3-kinase inhibition are regulated by transcription factors that are direct targets of GSK-3 regulation. In doing so, we have identified a transcriptional network downstream of GSK-3 signaling that regulates a subset of genes induced by PI 3-kinase inhibition in proliferating cells. In contrast, GSK-3 plays a much different role in cardiomyocytes, a terminally differentiated cell type. GSK-3 activity is known to inhibit the onset of cardiac hypertrophy in cardiomyocytes. When treated with phenylephrine, a hypertrophy inducing agent, cardiomyocytes experience an up-regulation of 131 unique genes as part of the hypertrophic response. Our studies show that direct inhibition of GSK-3 alone is sufficient to significantly up-regulate a subset of genes induced in the hypertrophic response of cardiomyocytes. Furthermore,we show that the transcription factor CREB, which is targeted by GSK-3 , binds and activates genes induced by direct GSK-3 inhibition.
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    Thesis (M.A.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
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