Roles of Nuclear Factor-κB, p53, and p21/WAF1 in Daunomycin-Induced Cell Cycle Arrest and Apoptosis1
- Anne-Cécile Hellin1,
- Mohamed Bentires-Alj1,
- Myriam Verlaet2,
- Valérie Benoit1,
- Jacques Gielen1,
- Vincent Bours and
- Marie-Paule Merville1
- 1Laboratory of Medical Chemistry and Medical Oncology (A.-C.H., M.B.-A., V.Be., J.G., V.Bo., M.-P.M.) and 2Laboratory of Pathological Anatomy (M.V.), University of Liège, Sart-Tilman, Liège, Belgium
Abstract
Daunomycin is a potent inducer of p53 and NF-κB transcription factors. It is also able to increase the amount of the p21 cyclin-dependent kinase inhibitor. The human p21 promoter harbors p53-responsive elements and an NF-κB binding site. We demonstrated, in human breast and colon carcinoma cells, the binding of NF-κB dimers to the κB site and the transcriptional activation of the human p21 promoter by daunomycin and by NF-κB subunits, thereby confirming the functionality of this κB binding site. However, using different tumor cell lines where p53 or NF-κB was inactive, we showed that p21 activation and cell cycle arrest induced by daunomycin was p53-dependent and NF-κB-independent, whereas daunomycin-induced apoptosis was p53- and NF-κB-independent.
Footnotes
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Send reprint requests to: M.-P. Merville, Medical Chemistry, Pathology B23, Sart-Tilman, 4000 Liège, Belgium. E-mail: mpmerville{at}ulg.ac.be
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↵1 This research was supported by grants from Télévie, the National Fund for Scientific Research, and the “Centre Anti-Cancéreux” (University of Liège, Belgium). A.-C.H. is a Research Assistant at the National Fund for Scientific Research (Belgium). V.Bo. is a Senior Research Associate and M.-P.M. is a Research Associate at the National Fund for Scientific Research (Belgium).
- Abbreviations:
- Cdk
- cyclin-dependent kinase
- WAF1
- wild-type p53-activated factor 1
- CIP1
- Cdk-interacting protein 1
- Gadd
- growth arrest and DNA damage
- STAT
- signal transducers and activators of transcription
- NF-κB
- nuclear factor-κB
- CMV
- cytomegalovirus
- HPV-16
- human papillomavirus type 16
- NAC
- N-acetylcysteine
- IκBα
- inhibitor κB α
- PDTC
- pyrrolidine-9-dithiocarbamate
- LUC
- luciferase
- CAT
- chloramphenicol acetyltransferase
- EMSA
- electrophoretic mobility shift assay
- FACS
- fluorescence-activated cell-sorting analysis
- RSV
- rous sarcoma virus
- ATCC
- American Type Culture Collection
- WST-1
- 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate
- OCT
- octamer binding protein
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- Received May 18, 2000.
- Accepted August 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
