EGF TGFB CONTROL OF SECOND MESSENGERS &TRANSCRIPTION

  • Magun, Bruce (PI)

    Project: Research project

    Project Details

    Description

    Little is known about the cellular mechanisms by which
    transforming growth factor beta (TGF-beta) is able to regulate
    the activities of nontransformed and neoplastic cells. Elucidation
    of the intracellular pathways of signal transduction should
    account for the wide variety of biological responses elicited by
    TGF-beta including both stimulatory actions such as the induction
    of anchorage-independent growth and neoplastic-like behavior in
    some types of cells and the inhibition of growth in other cell
    types. Studies from this laboratory have recently established that
    TGF-beta, when added in serum-free medium to quiescent Rat-1
    cells, will induce a large increase in inositol phosphate generation
    several hours later, and will dramatically sensitize the cells to the
    IP3-generating effects of EGF, which normally causes only a
    feeble increase in inositol phosphate levels. Concomitant with the
    increase in IP3 levels produced by EGF in TGF-beta-sensitized
    cells is an increase in the levels of free intracellular calcium, as
    determined by fura-2 microspectrafluorometry. In a similar time
    frame as phosphoinositide induction, TGF-beta will induce the
    transcriptional repression of transin, a transformation-associated
    metalloprotease whose transcription is activated by the action of
    several oncogenes and by EGF. In this application we propose to characterize the changes in
    phosphoinositide metabolism in nontransformed and transformed
    rat and mouse cell lines. We will investigate the ability of EGF
    and TGF-beta to induce the production of diacylglycerols and
    inositol phosphates and the mobilization of intracellular Ca2+.
    Potential TGF-beta-modulated pathways will be investigated,
    such as altered phospholipase C, DAG kinase and lipase activities.
    In an effort to understand the differentiatial responsiveness to
    TGF-beta of nontransformed and transformed cells, the
    intracellular responses of some oncogen-transformed and
    nontransformed cells to TGF-beta will be investigated. To
    correlate the alteration in 2nd messenger production with
    transcriptional repression induced by TGF-beta, alterations in
    transin transcription will be measured using nuclear run-on
    methods. Finally, in an effort to understand the regulation of
    transin transcription by both EGF and TGF-beta, transient
    expression assays will be performed using identified, and the
    nucleotide sequences responsible for mediating EGF- and TGF-
    beta-responsiveness of that gene will be identified. Thus, these
    studies should be able to relate the alterations in 2nd messenger
    production indeed by TGF-beta to the transcriptional
    responsiveness of a gene whose transcription in repressed by TGF-
    beta.
    StatusFinished
    Effective start/end date4/5/886/30/95

    Funding

    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health: $133,286.00
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health: $20,759.00

    ASJC

    • Medicine(all)

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