Abstract
The transcription factor nuclear factor-kappaB (NF-kappaB) regulates cell survival pathways, but the molecular mechanisms involved are not completely understood. Here, we developed a NF-kappaB reporter cell system derived from CEM T leukemic cells to monitor the consequences of NF-kappaB activation following DNA damage insults. Cells that activated NF-kappaB in response to ionizing radiation or etoposide arrested in the G2-M phase for a prolonged time, which was followed by increased cell cycle reentry and survival. In contrast, those that failed to activate NF-kappaB underwent transient G2-M arrest and extensive cell death. Importantly, p21waf1/cip1 was induced in S-G2-M phases in a NF-kappaB-dependent manner, and RNA interference of this cell cycle regulator reduced the observed NF-kappaB-dependent phenotypes. Thus, cell cycle-coupled induction of p21waf1/cip1 by NF-kappaB represents a resistance mechanism in certain cancer cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Breast Neoplasms / therapy
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Camptothecin / pharmacology
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Cell Survival
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Cyclin-Dependent Kinase Inhibitor p21
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Doxorubicin / pharmacology
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Enzyme Inhibitors / pharmacology
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Etoposide / pharmacology
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Female
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Flow Cytometry
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G2 Phase*
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Humans
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Mitosis*
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NF-kappa B / metabolism*
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Nucleic Acid Synthesis Inhibitors / pharmacology
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RNA Interference
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Radiation, Ionizing
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T-Lymphocytes / drug effects
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T-Lymphocytes / radiation effects
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Time Factors
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Antibiotics, Antineoplastic
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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NF-kappa B
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Nucleic Acid Synthesis Inhibitors
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Tumor Necrosis Factor-alpha
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Etoposide
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Doxorubicin
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Camptothecin