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Genomes and Genes
| ROLE FOR NF-KAPPA B IN RAS-MEDIATED ONCOGENESISSummaryPrincipal Investigator: ALBERT SIDNEY BALDWIN Affiliation: University of North Carolina Country: USA Abstract: The proto-oncogene ras is the most frequently mutated oncogene in human cancer, occurring in approximately 30% to 40% of all tumors. The ras genes encode small membrane associated GTP binding proteins that function in transmitting extracellular signals that regulate cell proliferation and differentiation. Ras activation or oncogenic mutation leads to the activation of signal transduction pathways that ultimately activate kinases that directly stimulate transcription factors such as Ets-1/2, Elk-1 or c-jun. These transcription factors then activate genes involved in controlling cellular proliferation. Recently, we have shown that expression of genes involved in immune and inflammatory responses, growing evidence indicates that this transcription factor and its family members are involved in controlling cellular proliferation. Typically, the activation of NF- kappaB (following treatment of cells with inflammatory cytokines, T cell activation signals, LPS, etc.) involves the targeted phosphorylation and degradation of the NF-kappaB inhibitor known as IkappaB, allowing nuclear translocation of NF-kappaB. However, we have show that both Ras and Raf transformed cells exhibit enhanced kappaB-dependent gene but do not exhibit enhanced nuclear translocation of NF-kappaB. Consistent with this observation, we find that the transcriptional activation function of the RelA/p65 subunit of NF-kappaB (existing in relatively low nuclear levels) is functionally activated in Ras or Raf transformed cells. Supportive of a role for NF-kappaB in mediating cellular transformation by Ras, we find that (a) expression of a super-repressor form of IkappBalpha blocks focus formation induced by oncogenic Ras, (b) p65 null fibroblast are inefficient at activating kappaB-dependent transcription in response to Ras, (c) the super-repressor IkappaBalpha blocks tumorigenesis of Ras-expressing and BCR-ABL- expressing tumor cell lines, and (d) inhibition of NF-kappaB function leads to apoptosis of Ras transformed cells. How NF-kappaB is target to respond to Ras and the exact role that NF-kappaB plays in controlling oncogenesis/tumorigenesis mediated by Ras are presently unknown. In order to address these questions and to explore the therapeutic potential of inhibiting NF-kappaB, the following aims are proposed: (1) determine how oncogenic Ras activates the transcription all activation function of NF-kappaB, (2) determine the role that NF- kappaB plays in controlling Ras mediated tumorigenesis and in controlling cell survival in response to Ras activation, and (3) determine if the inhibition of NF-kappaB, either alone or in combination with standard cancer therapies, will lead to significant tumor regression. The data will provide important new insights into regulation and function of a downstream effector of Ras signaling and will likely provide new therapeutic routes to cancer treatment. Funding Period: 1998-08-15 - 2004-01-31 more information: NIH RePORT Top Publications
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Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repressionRaquel Sitcheran
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599 7295, USA
EMBO J 24:510-20. 2005..Our data highlight the remarkable specificity of NF-kappaB activity to regulate gene expression in response to diverse cellular signals and have implications for glutamate homeostasis and neurodegenerative disease...- Maintenance of constitutive IkappaB kinase activity by glycogen synthase kinase-3alpha/beta in pancreatic cancerWillie Wilson
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, USA 27599 7295
Cancer Res 68:8156-63. 2008..These data provide new insight into GSK-3-dependent NF-kappaB regulation and further establish GSK-3 and IKK as potential therapeutic targets for pancreatic cancer... 
NF-kappaB pathways in the immune system: control of the germinal center reactionChristine A Goetz
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 405 West Dr, Room 213, Chapel Hill, NC 27599, USA
Immunol Res 41:233-47. 2008..We discuss potential mechanisms of action for Bcl-3 and Bcl-6 in this highly complex, but important process of B-cell affinity maturation...- Active roles for inhibitory kappaB kinases alpha and beta in nuclear factor-kappaB-mediated chemoresistance to doxorubicinBrian K Bednarski
Lineberger Comprehensive Cancer Center and Department of Surgery, University of North Carolina at Chapel Hill, 3010 Old Clinic Building, CB 7213, Chapel Hill, NC 27599 7213, USA
Mol Cancer Ther 7:1827-35. 2008..Moreover, we show that IKKalpha plays a critical role in NF-kappaB-mediated chemoresistance in response to doxorubicin and may serve as a potential target in combinational strategies to improve chemotherapeutic response... - Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-kappaBRaquel Sitcheran
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7295, USA
Mol Cell Biol 28:5061-70. 2008.... - Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKKHan C Dan
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Genes Dev 22:1490-500. 2008..The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin... 
Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammationKris A Steinbrecher
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
J Immunol 180:2588-99. 2008..We conclude that activation of RelA is required for homeostatic regulation of cell death and division in intestinal epithelia, as well as for protection from development of severe, acute inflammation of the intestine...- IkappaB kinase beta inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cellsElizabeth A Duncan
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Mol Cancer Ther 7:391-7. 2008..These data indicate that blockage of BCR-ABL-induced NF-kappaB activation via IkappaB kinase beta inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia... - Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoterMichael Witcher
Lady Davis Institute for Medical Research, Segal Cancer Centre of the SMBD Jewish General Hospital, McGill University, Montreal H3T1E2, Quebec, Canada
Nucleic Acids Res 36:435-43. 2008.... - Expression of nuclear factor-kappaB family proteins in hepatocellular carcinomasBERT H O'NEIL
Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Oncology 72:97-104. 2007..Recent information has implicated IkappaB family members (e.g. Bcl-3) as possible mediators of NF-kappaB activation. Therefore, we examined the expression of all NF-kappaB family members and downstream targets in HCC... - LZAP, a putative tumor suppressor, selectively inhibits NF-kappaBJialiang Wang
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
Cancer Cell 12:239-51. 2007..In aggregate, these data support a role of LZAP in NF-kappaB regulation and tumor suppression... - Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alphaHan C Dan
Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Cancer Res 67:6263-9. 2007..The results indicate a novel role for IKK alpha in controlling mTOR function in cancer cells with constitutive Akt activity... - IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylationMazhar Adli
Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
J Biol Chem 281:26976-84. 2006..The data indicate a role for IKK-i/IKKepsilon in controlling proliferation of certain cancer cells through regulation of constitutive NF-kappaB activity... - The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylationElizabeth A Duncan
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA
J Biol Chem 281:12521-5. 2006..These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression... - Expression of the Bcl-3 proto-oncogene suppresses p53 activationDavid Kashatus
Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Genes Dev 20:225-35. 2006.... - Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcriptionKris A Steinbrecher
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Mol Cell Biol 25:8444-55. 2005..Therefore, GSK-3beta has profound effects on transcription in a gene-specific manner through a mechanism involving control of promoter-specific recruitment of NF-kappaB... - Addressing reported pro-apoptotic functions of NF-kappaB: targeted inhibition of canonical NF-kappaB enhances the apoptotic effects of doxorubicinBrian K Bednarski
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
PLoS ONE 4:e6992. 2009..Therefore, combination therapies incorporating NF-kappaB inhibitors together with standard chemotherapies remains a viable method to improve the clinical outcomes in patients with advanced stage malignancies...