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Science 5 December 1997:
Vol. 278. no. 5344, pp. 1812 - 1815
DOI: 10.1126/science.278.5344.1812
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Reports

Requirement of NF-kappa B Activation to Suppress p53-Independent Apoptosis Induced by Oncogenic Ras

Marty W. Mayo, Cun-Yu Wang, Patricia C. Cogswell, Kelley S. Rogers-Graham, Scott W. Lowe, Channing J. Der, Albert S. Baldwin Jr. *

The ras proto-oncogene is frequently mutated in human tumors and functions to chronically stimulate signal transduction cascades resulting in the synthesis or activation of specific transcription factors, including Ets, c-Myc, c-Jun, and nuclear factor kappa B (NF-kappa B). These Ras-responsive transcription factors are required for transformation, but the mechanisms by which these proteins facilitate oncogenesis have not been fully established. Oncogenic Ras was shown to initiate a p53-independent apoptotic response that was suppressed through the activation of NF-kappa B. These results provide an explanation for the requirement of NF-kappa B for Ras-mediated oncogenesis and provide evidence that Ras-transformed cells are susceptible to apoptosis even if they do not express the p53 tumor-suppressor gene product.

M. W. Mayo and P. C. Cogswell, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
C.-Y. Wang, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine; Curriculum in Genetics and Molecular Biology; and Department of Endodontics, University of North Carolina School of Dentistry, Chapel Hill, NC 27599, USA.
K. S. Rogers-Graham, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
S. W. Lowe, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
C. J. Der, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine; Curriculum in Genetics and Molecular Biology; and Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
A. S. Baldwin, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine; Curriculum in Genetics and Molecular Biology; and Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
*   To whom correspondence should be addressed at Lineberger Comprehensive Cancer Center, Campus Box 7295, University of North Carolina, Chapel Hill, NC 27599, USA.

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Positive and Negative Regulation of NF-kappa B by COX-2. ROLES OF DIFFERENT PROSTAGLANDINS.
B. Poligone and A. S. Baldwin (2001)
J. Biol. Chem. 276, 38658-38664
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Frequent Epigenetic Inactivation of RASSF1A by Aberrant Promoter Hypermethylation in Human Gastric Adenocarcinoma.
D.-S. Byun, M.-G. Lee, K.-S. Chae, B.-G. Ryu, and S.-G. Chi (2001)
Cancer Res. 61, 7034-7038
   Abstract »    Full Text »    PDF »
Cyclooxygenase-independent actions of cyclooxygenase inhibitors.
I. TEGEDER, J. PFEILSCHIFTER, and G. GEISSLINGER (2001)
FASEB J 15, 2057-2072
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The E2A-HLF Oncoprotein Activates Groucho-Related Genes and Suppresses Runx1.
J. Dang, T. Inukai, H. Kurosawa, K. Goi, T. Inaba, N. T. Lenny, J. R. Downing, S. Stifani, and A. T. Look (2001)
Mol. Cell. Biol. 21, 5935-5945
   Abstract »    Full Text »    PDF »
Frequent Epigenetic Inactivation of RASSF1A in Human Bladder Carcinoma.
M.-G. Lee, H.-Y. Kim, D.-S. Byun, S.-J. Lee, C.-H. Lee, J. I. Kim, S.-G. Chang, and S.-G. Chi (2001)
Cancer Res. 61, 6688-6692
   Abstract »    Full Text »    PDF »
Acute Pancreatitis Signals Activation of Apoptosis-Associated and Survival Genes inMice.
G. Gomez, H.-M. Lee, Q. He, E. W. Englander, T. Uchida, and G. H. Greeley Jr. (2001)
Experimental Biology and Medicine 226, 692-700
   Abstract »    Full Text »    PDF »
Natural Biology of Polyomavirus Middle T Antigen.
K. A. Gottlieb and L. P. Villarreal (2001)
Microbiol. Mol. Biol. Rev. 65, 288-318
   Abstract »    Full Text »    PDF »
The Recruitment of Fas-associated Death Domain/Caspase-8 in Ras-induced Apoptosis.
C.-Y. Chen, P. Juo, J. S. Liou, C.-Q. Li, Q. Yu, J. Blenis, and D. V. Faller (2001)
Cell Growth Differ. 12, 297-306
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Nuclear Factor-{{kappa}}B Is Constitutively Active in C-Cell Carcinoma and Required for RET-induced Transformation.
L. Ludwig, H. Kessler, M. Wagner, C. Hoang-Vu, H. Dralle, G. Adler, B. O. Bohm, and R. M. Schmid (2001)
Cancer Res. 61, 4526-4535
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Inhibition of NF-{kappa}B sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis.
D. R. Jones, R. M. Broad, L. V. Madrid, A. S. Baldwin Jr, and M. W. Mayo (2000)
Ann. Thorac. Surg. 70, 930-936
   Abstract »    Full Text »    PDF »
The NF-{kappa}B Cascade Is Important in Bcl-xL Expression and for the Anti-Apoptotic Effects of the CD28 Receptor in Primary Human CD4+ Lymphocytes.
A. Khoshnan, C. Tindell, I. Laux, D. Bae, B. Bennett, and A. E. Nel (2000)
J. Immunol. 165, 1743-1754
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Role of the Ikappa B Kinase Complex in Oncogenic Ras- and Raf-Mediated Transformation of Rat Liver Epithelial Cells.
M. Arsura, F. Mercurio, A. L. Oliver, S. S. Thorgeirsson, and G. E. Sonenshein (2000)
Mol. Cell. Biol. 20, 5381-5391
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The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies.
T. G. Willis and M. J. S. Dyer (2000)
Blood 96, 808-822
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Chemopreventive Properties of trans-Resveratrol Are Associated with Inhibition of Activation of the I{{kappa}}B Kinase.
M. Holmes-McNary and A. S. Baldwin Jr. (2000)
Cancer Res. 60, 3477-3483
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alpha 5beta 1 Integrin Protects Intestinal Epithelial Cells from Apoptosis through a Phosphatidylinositol 3-Kinase and Protein Kinase B-dependent Pathway.
J. W. Lee and R.L. Juliano (2000)
Mol. Biol. Cell 11, 1973-1987
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Functional Isoforms of Ikappa B Kinase alpha (IKKalpha ) Lacking Leucine Zipper and Helix-Loop-Helix Domains Reveal that IKKalpha and IKKbeta Have Different Activation Requirements.
F. R. McKenzie, M. A. Connelly, D. Balzarano, J. R. Müller, R. Geleziunas, and K. B. Marcu (2000)
Mol. Cell. Biol. 20, 2635-2649
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Disruption of Hsp90 Function Results in Degradation of the Death Domain Kinase, Receptor-interacting Protein (RIP), and Blockage of Tumor Necrosis Factor-induced Nuclear Factor-kappa B Activation.
J. Lewis, A. Devin, A. Miller, Y. Lin, Y. Rodriguez, L. Neckers, and Z.-g. Liu (2000)
J. Biol. Chem. 275, 10519-10526
   Abstract »    Full Text »    PDF »
Akt Suppresses Apoptosis by Stimulating the Transactivation Potential of the RelA/p65 Subunit of NF-kappa B.
L. V. Madrid, C.-Y. Wang, D. C. Guttridge, A. J. G. Schottelius, A. S. Baldwin Jr., and M. W. Mayo (2000)
Mol. Cell. Biol. 20, 1626-1638
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Fas cross-linking induces apoptosis in human airway smooth muscle cells.
K. J. Hamann, J. E. Vieira, A. J. Halayko, D. Dorscheid, S. R. White, S. M. Forsythe, B. Camoretti-Mercado, K. F. Rabe, and J. Solway (2000)
Am J Physiol Lung Cell Mol Physiol 278, L618-L624
   Abstract »    Full Text »    PDF »
A Subclass of Ras Proteins That Regulate the Degradation of IB.
C. Fenwick, S. Na, R. E. Voll, H. Zhong, S. Im, J. W. Lee, and S. Ghosh (2000)
Science 287, 869-873
   Abstract »    Full Text »
Up-regulation of Multidrug Resistance P-glycoprotein via Nuclear Factor-kappa B Activation Protects Kidney Proximal Tubule Cells from Cadmium- and Reactive Oxygen Species-induced Apoptosis.
F. Thevenod, J. M. Friedmann, A. D. Katsen, and I. A. Hauser (2000)
J. Biol. Chem. 275, 1887-1896
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A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma.
T. T. Chou, J. Q. Trojanowski, and V. M.-Y. Lee (2000)
J. Biol. Chem. 275, 565-570
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Dependence of Dbl and Dbs Transformation on MEK and NF-kappa B Activation.
I. P. Whitehead, Q. T. Lambert, J. A. Glaven, K. Abe, K. L. Rossman, G. M. Mahon, J. M. Trzaskos, R. Kay, S. L. Campbell, and C. J. Der (1999)
Mol. Cell. Biol. 19, 7759-7770
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Lack of Involvement of Ataxia Telangiectasia Mutated (ATM) in Regulation of Nuclear Factor-{{kappa}}B (NF-{{kappa}}B) in Human Diploid Fibroblasts.
B. P. Ashburner, R. E. Shackelford, A. S. Baldwin Jr., and R. S. Paules (1999)
Cancer Res. 59, 5456-5460
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Ras Proteins: Recent Advances and New Functions.
A. Rebollo and C. Martinez-A (1999)
Blood 94, 2971-2980
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Oncogenic Ras Sensitizes Cells to Apoptosis by Par-4.
A. Nalca, S. G. Qiu, N. El-Guendy, S. Krishnan, and V. M. Rangnekar (1999)
J. Biol. Chem. 274, 29976-29983
   Abstract »    Full Text »    PDF »
Alterations of SAG mRNA in human cancer cell lines: requirement for the RING finger domain for apoptosis protection.
Y. Sun (1999)
Carcinogenesis 20, 1899-1903
   Abstract »    Full Text »    PDF »


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