کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1426039 1509081 2009 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Controlling subcellular localization to alter function: Sending oncogenic Bcr–Abl to the nucleus causes apoptosis
موضوعات مرتبط
مهندسی و علوم پایه مهندسی مواد بیومتریال
پیش نمایش صفحه اول مقاله
Controlling subcellular localization to alter function: Sending oncogenic Bcr–Abl to the nucleus causes apoptosis
چکیده انگلیسی

Altering the subcellular localization of signal transducing proteins is a novel approach for therapeutic intervention. Mislocalization of tumor suppressors, oncogenes, or factors involved in apoptosis results in aberrant functioning of these proteins, leading to disease. In the case of chronic myelogenous leukemia (CML), cytoplasmic Bcr–Abl causes oncogenesis/proliferation. On the other hand, nuclear entrapment of endogenous Bcr–Abl (in K562 human leukemia cells) causes apoptosis. The goal of this study was to determine whether ectopically expressed Bcr–Abl could cause apoptosis of K562 cells when specifically directed to the nucleus via strong nuclear localization signals (NLSs). A single NLS from SV40 large T-antigen or four NLSs were subcloned to Bcr–Abl (1NLS–Bcr–Abl or 4NLS–Bcr–Abl). When transfected into K562 cells, only 4NLS–Bcr–Abl translocated to the nucleus. Bcr–Abl alone was found to localize in the cell cytoplasm, colocalizing with actin due to its actin binding domain. 1NLS–Bcr–Abl also localized with actin. Apoptosis induced by 4NLS–Bcr–Abl was evaluated 24 h post-transfection by morphologic determination, DNA staining, and caspase-3 assay. This is the first demonstration that altering the location of ectopically expressed Bcr–Abl can kill leukemia cells. Multiple NLSs are required to overcome Bcr–Abl binding to actin, thus driving it into the nucleus and causing apoptosis.

Bcr–Abl with 4 nuclear localization signals localizes to the nucleus (middle panel) and causes apoptosis (first and last panels; apoptosis indicated by arrows). Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Controlled Release - Volume 140, Issue 3, 16 December 2009, Pages 245–249
نویسندگان
, , , , , ,