کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2515884 1118579 2008 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Enforced expression of the tumor suppressor p53 renders human leukemia cells (U937) more sensitive to 1-[β-d-arabinofuranosyl]cytosine (ara-C)-induced apoptosis
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Enforced expression of the tumor suppressor p53 renders human leukemia cells (U937) more sensitive to 1-[β-d-arabinofuranosyl]cytosine (ara-C)-induced apoptosis
چکیده انگلیسی

The effects of enforced expression of p53 on the sensitivity of p53−/− human monocytic leukemia cells (U937) to apoptosis following exposure to the S-phase-specific antimetabolite 1-[β-d-arabinofuranosyl]cytosine (ara-C) were examined. Cells were stably transfected with a plasmid containing a chimeric DNA construct encoding a temperature-sensitive p53 variant (135ala⇒val), which transactivates at 32° but is non-functional at 37°. A significant reduction in the S-phase population was observed in ptsp53 mutants incubated at 32°. Nevertheless, while vector controls did not exhibit differential sensitivity to ara-C at 32° versus 37°, temperature-sensitive p53 mutants displayed a significant increase in apoptosis at the permissive temperature. This was not accompanied by increased ara-CTP formation, DNA incorporation of []ara-C, or altered expression of Bcl-2 or Bax. Enhanced sensitivity was associated with increased mitochondrial injury (e.g. cytochrome c release), caspase activation, and loss of clonogenic survival. Significantly, ptsp53 cells synchronized in S phase were markedly more sensitive to ara-C-mediated mitochondrial injury and apoptosis at 32°, indicating that wild-type p53 specifically enhances the susceptibility of this subpopulation to ara-C lethality. Consistent with these results, transient transfection of human wild-type p53 cDNA rendered parental U937 cells more sensitive to ara-C-mediated cell death. Collectively, these findings indicate that p53 expression renders S-phase U937 cells more susceptible to ara-C-mediated mitochondrial dysfunction, cytochrome c release, apoptosis, and loss of clonogenic survival without enhancing ara-C metabolism. Such findings raise the possibility that loss of functional p53 activity allows leukemia cells to circumvent ara-C lethality.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 65, Issue 12, 15 June 2003, Pages 1997–2008
نویسندگان
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