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. pmc Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia
    Matthew J Cooper
    Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 8:e66755. 2013
  2. pmc GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB
    Deepali Bang
    Department of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
    Cancer Discov 3:690-703. 2013
  3. doi Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells
    M F Kendellen
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
    Oncogene 33:1297-305. 2014
  4. pmc Development of a high-throughput assay for identifying inhibitors of TBK1 and IKKε
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America
    PLoS ONE 7:e41494. 2012
  5. pmc Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha
    E C Merkhofer
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 29:1238-48. 2010
  6. pmc IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF-induced/canonical pathway
    Mazhar Adli
    Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 5:e9428. 2010
  7. pmc Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis
    Daniela S Bassères
    Lineberger Comprehensive Cancer Center and Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA
    Cancer Res 70:3537-46. 2010
  8. pmc IKK-dependent, NF-κB-independent control of autophagic gene expression
    W C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:1727-32. 2011
  9. pmc NF-κB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death
    S J Stein
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:4557-66. 2011
  10. pmc p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation
    William C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Mol Cell 45:719-30. 2012

Scientific Experts

  • ALBERT SIDNEY BALDWIN
  • W H Miller
  • Hong Jin Kim
  • Bert O'Neil
  • Raquel Sitcheran
  • Kris A Steinbrecher
  • Christine A Goetz
  • Jessica E Hutti
  • Mazhar Adli
  • Brian K Bednarski
  • Patricia Cogswell
  • Han C Dan
  • Elizabeth A Duncan
  • Matthew J Cooper
  • Willie Wilson
  • M F Kendellen
  • Deepali Bang
  • William C Comb
  • Lewis C Cantley
  • W C Comb
  • S J Stein
  • P Cogswell
  • Daniela S Bassères
  • E C Merkhofer
  • Michael Witcher
  • Jialiang Wang
  • David Kashatus
  • K S Clark
  • C L Lawrence
  • J W Bradford
  • Eric I Zimmerman
  • Jen Jen Yeh
  • Gary L Johnson
  • Martin C Whittle
  • Thien A Nguyen
  • Sreerupa Ghose Roy
  • James S Duncan
  • Brian J Dewar
  • Richard I Christopherson
  • Lee M Graves
  • Stephen V Frye
  • Pei Fen Kuan
  • Jian Jin
  • Nathan J Cox
  • Meagan Ryan
  • Kristy L Richards
  • Lauren S Jones
  • David M Smalley
  • Dmitri Kireev
  • Adam D Pfefferle
  • Adam W Cheely
  • Sean C Russell
  • Melissa A Porter
  • Xiaodong Wang
  • Charles M Perou
  • Mayukh Sircar
  • William P Janzen
  • Evan Merkhofer
  • Aaron Ebbs
  • Elena Levantini
  • Charles L Sawyers
  • Leslie Summers-Deluca
  • Joseph A Duncan
  • Jenny P Y Ting
  • Katie J Mayo
  • Filippa Pettersson
  • Brian J Skaggs
  • Karl Ziegelbauer
  • Xiaoyu Ding
  • Sarah J Stein
  • Kavita Coombe
  • Daphné Dupéré-Richer
  • Patricia C Cogswell
  • Alessandra Padovani
  • Wendell G Yarbrough
  • Marty W Mayo
  • Hanbing An
  • Vasiliki Anest

Detail Information

Publications29

  1. pmc Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia
    Matthew J Cooper
    Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 8:e66755. 2013
    ..These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition. ..
  2. pmc GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB
    Deepali Bang
    Department of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
    Cancer Discov 3:690-703. 2013
    ..These data identify GSK-3α as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-κB signaling pathways...
  3. doi Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells
    M F Kendellen
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
    Oncogene 33:1297-305. 2014
    ..The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. ..
  4. pmc Development of a high-throughput assay for identifying inhibitors of TBK1 and IKKε
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America
    PLoS ONE 7:e41494. 2012
    ..Together, these data describe a new high-throughput screening assay which will facilitate the discovery of small molecule TBK1/IKKε inhibitors possessing therapeutic potential for both inflammatory diseases and cancer...
  5. pmc Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha
    E C Merkhofer
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 29:1238-48. 2010
    ..In addition this work indicates the importance of IKKalpha as a mediator of Her2-induced tumor progression...
  6. pmc IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF-induced/canonical pathway
    Mazhar Adli
    Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 5:e9428. 2010
    ..These conclusions have led to a focus on development of IKKbeta inhibitors for potential use in inflammatory disorders and cancer...
  7. pmc Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis
    Daniela S Bassères
    Lineberger Comprehensive Cancer Center and Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA
    Cancer Res 70:3537-46. 2010
    ..Taken together, these results show the importance of the NF-kappaB subunit p65/RelA in K-Ras-induced lung transformation and identify IKKbeta as a potential therapeutic target for K-Ras-induced lung cancer...
  8. pmc IKK-dependent, NF-κB-independent control of autophagic gene expression
    W C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:1727-32. 2011
    ..Thus, IKK likely has multiple roles in response to starvation by regulating NF-κB-dependent antiapoptotic gene expression as well as controlling expression of autophagic genes through a yet undetermined mechanism...
  9. pmc NF-κB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death
    S J Stein
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:4557-66. 2011
    ..The data demonstrate that one function for NF-κB in oncogenesis is the suppression of oncoprotein-induced ROS levels and that inhibition of NF-κB in some cancers, including CML, will increase ROS levels and promote cell death...
  10. pmc p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation
    William C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Mol Cell 45:719-30. 2012
    ..Finally, leucine deprivation is shown to be necessary and sufficient for starvation-induced, IKK-mediated p85 phosphorylation and PI3K feedback inhibition...
  11. pmc Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina at Chapel Hill, North Carolina 27599, USA
    Cancer Res 72:3260-9. 2012
    ..These data also indicate that NF-κB plays diverse roles downstream from different oncogenic signaling pathways...
  12. pmc 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...
  13. pmc 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...
  14. doi 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...
  15. pmc 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...
  16. pmc 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. pmc 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
    ....
  18. 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...
  19. 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...
  20. 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...
  21. 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...
  22. 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...
  23. pmc 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
    ....
  24. doi 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...
  25. 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...
  26. pmc 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...
  27. pmc 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
    ....
  28. pmc 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...