ROLE FOR NF-KAPPA B IN RAS-MEDIATED ONCOGENESIS

Summary

Principal 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

  1. ncbi Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression
    Raquel Sitcheran
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599 7295, USA
    EMBO J 24:510-20. 2005
  2. ncbi Maintenance of constitutive IkappaB kinase activity by glycogen synthase kinase-3alpha/beta in pancreatic cancer
    Willie 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
  3. ncbi NF-kappaB pathways in the immune system: control of the germinal center reaction
    Christine 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
  4. ncbi Active roles for inhibitory kappaB kinases alpha and beta in nuclear factor-kappaB-mediated chemoresistance to doxorubicin
    Brian 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
  5. ncbi Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-kappaB
    Raquel 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
  6. ncbi Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK
    Han 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
  7. ncbi Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation
    Kris 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
  8. ncbi IkappaB kinase beta inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells
    Elizabeth 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
  9. ncbi Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter
    Michael 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
  10. ncbi Expression of nuclear factor-kappaB family proteins in hepatocellular carcinomas
    BERT 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

Scientific Experts

  • Bert O'Neil
  • Raquel Sitcheran
  • Kris A Steinbrecher
  • Christine A Goetz
  • Albert S Baldwin
  • Brian K Bednarski
  • Han C Dan
  • Elizabeth A Duncan
  • Mazhar Adli
  • Willie Wilson
  • Michael Witcher
  • Jialiang Wang
  • David Kashatus
  • Patricia Cogswell
  • Hong Jin Kim
  • Jenny P-Y Ting
  • Karl Ziegelbauer
  • Charles L Sawyers
  • Leslie Summers-Deluca
  • Joseph A Duncan
  • Jenny P Y Ting
  • Xiaoyu Ding
  • Katie J Mayo
  • Sarah J Stein
  • Filippa Pettersson
  • Brian J Skaggs
  • Kavita Coombe
  • Daphné Dupéré-Richer
  • Patricia C Cogswell
  • Matthew J Cooper
  • Hong J Kim
  • Alessandra Padovani
  • Wilson H Miller
  • Wendell G Yarbrough
  • Marty W Mayo
  • Hanbing An
  • Vasiliki Anest

Detail Information

Publications17

  1. ncbi Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression
    Raquel 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...
  2. ncbi Maintenance of constitutive IkappaB kinase activity by glycogen synthase kinase-3alpha/beta in pancreatic cancer
    Willie 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...
  3. ncbi NF-kappaB pathways in the immune system: control of the germinal center reaction
    Christine 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...
  4. ncbi Active roles for inhibitory kappaB kinases alpha and beta in nuclear factor-kappaB-mediated chemoresistance to doxorubicin
    Brian 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...
  5. ncbi Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-kappaB
    Raquel 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
    ....
  6. ncbi Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK
    Han 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...
  7. ncbi Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation
    Kris 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...
  8. ncbi IkappaB kinase beta inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells
    Elizabeth 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...
  9. ncbi Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter
    Michael 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
    ....
  10. ncbi Expression of nuclear factor-kappaB family proteins in hepatocellular carcinomas
    BERT 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...
  11. ncbi LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB
    Jialiang 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...
  12. ncbi Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha
    Han 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...
  13. ncbi IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylation
    Mazhar 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...
  14. ncbi The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation
    Elizabeth 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...
  15. ncbi Expression of the Bcl-3 proto-oncogene suppresses p53 activation
    David 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
    ....
  16. ncbi Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription
    Kris 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...
  17. ncbi Addressing reported pro-apoptotic functions of NF-kappaB: targeted inhibition of canonical NF-kappaB enhances the apoptotic effects of doxorubicin
    Brian 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...