The pathway of leukemic cell death caused by glucocorticoid receptor fragment 465

Mohamed El-Naghy, Betty H. Johnson, Hong Chen, Naseem H. Ansari, Weiping Zhang, Peter Moller, Yan shan Ji, E. Brad Thompson

    Research output: Contribution to journalArticle

    11 Scopus citations

    Abstract

    The truncated glucocorticoid receptor mutant gene 465* codes for a protein that is interrupted by a frameshift mutation in the second zinc finger of the natural DNA binding domain. Thus, 465* represents the natural amino acid sequence 1-465 followed by 21 novel amino acids starting at position 466. The entire ligand binding domain is missing. Prior studies have shown that transient transfection of the glucocorticoid-resistant leukemic T-cell clone ICR-27 with a plasmid expressing 465* rapidly reduces the number of viable cells. This response does not require activation by a steroid, and a hybrid protein consisting of green fluorescent protein fused to 465* is found primarily in the cytoplasm. In the present study, we present evidence that the decrease in cell number is due to a form of cell death that bears many of the classic characteristics of apoptosis. Expression of the 465* protein can be detected a few hours after electroporation and is followed by activation of caspase-3 as well as reduction of the mitochondrial inner transmembrane potential. The caspase-3 inhibitor ZVAD.fmk blocks 465*-dependent cell death when added acutely after electroporation, but fails to do so later. We conclude that the novel 465* gene causes cell death by apoptosis.

    Original languageEnglish (US)
    Pages (from-to)166-175
    Number of pages10
    JournalExperimental Cell Research
    Volume270
    Issue number2
    DOIs
    StatePublished - Nov 1 2001

    Keywords

    • Apoptosis
    • Caspase-3
    • Glucocorticoid receptor fragment
    • Mitochondria
    • T-cell leukemia

    ASJC Scopus subject areas

    • Cell Biology

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