Enhanced G2-M arrest by nuclear factor-{kappa}B-dependent p21waf1/cip1 induction.
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.
Department of Pharmacology, University of Wisconsin, 301 Service Memorial Institute, 1300 University Avenue, Madison, WI 53706, USA.
Shelly M
SM
Wuerzberger-Davis
Pei-Yun
PY
Chang
Craig
C
Berchtold
Shigeki
S
Miyamoto
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D008938:Mitosis; D016328:NF-kappa B / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011839:Radiation, Ionizing; D013601:T-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D019384:Nucleic Acid Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D004317:Doxorubicin; D002166:Camptothecin