Oncogenic Ha-Ras-induced Signaling Activates NF-κB Transcriptional Activity, Which Is Required for Cellular Transformation*
- Timothy S. Fincoद,
- John K. Westwick‡‖**,
- Jacqueline L. Norris‡‡,
- Amer A. Beg§§,
- Channing J. Der‡§‖ and
- Albert S. Baldwin, Jr.‡§¶¶,166
- From the ‡Lineberger Comprehensive Cancer Center,§Curriculum in Genetics and Molecular Biology,‖Department of Pharmacology, and ¶¶Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599-7295 and the §§Department of Biological Sciences, Columbia University, New York, New York 10027
Abstract
Ras proteins function in stimulating cell proliferation and differentiation through the activation of Raf-dependent and Raf-independent signal transduction pathways and the subsequent activation of specific transcription factors. The transcription factor NF-κB has been widely studied as a regulator of genes involved in immune and inflammatory responses. A variety of stimuli activate NF-κB through the induced phosphorylation and degradation of the inhibitor IκB followed by nuclear translocation of NF-κB. We show here that oncogenic forms of Ha-Ras activate NF-κB, not through induced nuclear translocation, but rather through the activation of the transcriptional function of the NF-κB RelA/p65 subunit. Importantly, RelA/p65 −/− cells are inefficient in the activation of κB-dependent gene expression in response to oncogenic Ras expression. Furthermore, IκBα expression blocks focus formation in NIH3T3 cells induced by oncogenic Ras. These results demonstrate that NF-κB is a critical downstream mediator of Ha-Ras signaling and oncogenic potential.
Footnotes
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↵* This research was supported by National Institutes of Health Grants CA72771 (to A. S. B.) and CA69577 (to C. J. D.) and by Department of the Army Grant DAMD-94-J-405 (to A. S. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ Present address: Howard Hughes Medical Inst., University of California, San Francisco, CA 94143.
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↵** Lineberger Cancer Center Fellow during the course of this work. Present address: Signal Pharmaceuticals, San Diego, CA 92121.
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↵‡ Supported by a National Institutes of Health postdoctoral fellowship.
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↵166 To whom correspondence should be addressed: Lineberger Comprehensive Cancer Center, CB# 7295, University of North Carolina School of Medicine, Chapel Hill, NC 27599. Tel.: 919-966-3652; Fax: 919-966-0444.
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↵1 The abbreviations used are: MEK, MAP/ERK kinase; ERK, extracellular signal-regulated kinase; JNK, Jun kinase; CAT, chloramphenicol acetyltransferase; HIV, human immunodeficiency virus; LTR, long terminal repeat; DHFR, dihydrofolate reductase; EMSA, electrophoretic mobility shift assay; CMV, cytomegalovirus.
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↵2 J. Norris and A. S. Baldwin, Jr., unpublished observations.
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↵3 M. Mayo and A. S. Baldwin, Jr., submitted for publication.
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- Received June 16, 1997.
- Revision received July 22, 1997.
