The MDR1 enhancesome--its activation and inhibition

    Project Details

    Description

    DESCRIPTION: (Application Abstract) P-glycoprotein (Pgp) was first identified
    by virtue of its overexpression in multidrug-resistant cells, where it mediates
    the efflux of a large number of chemotherapeutic agents. Moreover, recent
    evidence suggests that Pgp may also play a more general anti-apoptotic role in
    tumor cells, since cells overexpressing Pgp also exhibit resistance to a number
    of other caspase-mediated apoptotic inducers, including serum starvation, UV
    irradiation, Fas ligand and TNF. Interestingly, many of these agents also act
    as inducers of Pgp transcription, suggesting that activation of Pgp may be part
    of a general "stress response" of tumor cells, and play a role in cellular
    growth and death decisions in response to toxic stimuli. Our laboratory has had
    a long-standing interest in the mechanisms regulating the transcription of the
    human Pgp gene, MDR1. Our recent observation that MDR1 gene expression can be
    rapidly (within minutes) activated within patient tumors exposed to the
    genotoxic chemotherapeutic agent doxorubicin has prompted us to investigate the
    mechanism underlying transcriptional induction of MDR1 by a variety of "stress"
    agents. Surprisingly, we have found that signals from seemingly disparate
    agents (including chromatin modifiers, differentiation agents,
    chemotherapeutics and UV irradiation) converge on a small region of the MDR1
    promoter, and have found that this region interacts with a multisubunit
    complex, which we refer to as the "MDR1 enhancesome," that includes the
    transcription factors NF-Y, Sp1 and PCAF. Furthermore, we have identified a
    novel chemotherapeutic agent, ET-743, which inhibits activation of MDR1 through
    the enhancesome, without significantly affecting constitutive MDR1
    transcription. We now propose to continue our investigations of the "MDR1
    enhancesome" and ET-743: 1) To identify and characterize additional components
    of the "MDR1 enhancesome"; 2) To investigate the effect of transcriptional
    inducers on chromatin remodeling at the MDR1 promoter; 3) To pursue our finding
    that multiple Sp1 family members may be components of the MDR1 enhancesome and
    have divergent effects on MDR1 transcription and 4) To continue to investigate
    the mechanism by which ET-743 inhibits activation of MDR1 transcription, with
    the long-term goal of identifying the specific transcriptional target of this
    novel chemotherapeutic agent.
    StatusFinished
    Effective start/end date3/1/943/31/06

    Funding

    • National Cancer Institute: $125,961.00
    • National Cancer Institute
    • National Cancer Institute
    • National Cancer Institute
    • National Cancer Institute
    • National Cancer Institute: $222,639.00
    • National Cancer Institute: $348,600.00
    • National Cancer Institute
    • National Cancer Institute: $314,985.00
    • National Cancer Institute: $164,264.00
    • National Cancer Institute
    • National Cancer Institute
    • National Cancer Institute: $214,828.00
    • National Cancer Institute: $243,276.00
    • National Cancer Institute

    ASJC

    • Genetics
    • Molecular Biology

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