Faculty: Shigeki Miyamoto, PhD
Our laboratory studies regulation of the transcription factor NF-kB as a model system to learn how normal growth control and cell death are regulated and how deregulation of such processes may contribute to development of cancer. NF-kB is normally sequestered in the cytoplasm by an inhibitor protein, IkB. A variety of extracellular signals induce rapid release of IkB from NF-kB, thereby allowing nuclear translocation of NF-kB to activate target gene expression. The products of these NF-kB target genes regulate diverse biological processes, including immune function, growth control and apoptosis. We are currently investigating the following three specific areas of research:
- What is the mechanism and consequence of NF-kB activation by nuclear DNA damage? Activation of cytoplasmically localized NF-kB by DNA damaging agents suggests that DNA-damage in the nucleus may generate a signal that is transduced out to the cytoplasm--the reverse of classical NF-kB activation pathways. We are investigating the components and biochemical processes involved in this signaling pathway using DNA damaging anti-cancer agents (i.e., ionizing radiation and topoisomerase I and II inhibitors). We are also investigating the potential utility of this pathway in enhancing current methods of anti-cancer treatments.
- What is the mechanism of constitutive NF-kB activation during B cell development and in human cancers? We have recently discovered a novel mechanism of IkB degradation involved in constitutive NF-kB activation. We are looking to identify the IkB protease and its regulatory pathways during B cell development and in human cancer cells.
- How is the localization of inactive NF-kB/IkB complexes regulated? We have shown that dominant nuclear export over weaker nuclear import maintains inactive NF-kB/IkBacomplexes in the cytoplasm. We are currently investigating the regulatory mechanisms involved in this process and biological consequences when this novel NF-kB regulatory mechanism is disrupted.
Honors & Awards
- H.I. Romnes Faculty Fellow
- Yang B, Wagner J, Damaschke N, Yao T, Wuerzberger-Davis SM, Lee MH, Svaren J, Miyamoto S, Jarrard DF. (2014) A novel pathway links oxidative stress to loss of insulin growth factor-2 (IGF2) imprinting through NF-κB activation. PLoS One. 9(2):e88052. eCollection 2014. PMID: 24558376 [PubMed - in process]
- Pak C and Miyamoto S (2013). A New Alpha in Line Between KRAS and NF-κB Activation? Cancer Discov. 3:613-615.
- Hebron E, Hope C, Kim J, Jensen JL, Flanagan C, Bhatia N, Maroulakou I, Mitsiades C, Miyamoto S, Callander N, Hematti P, and Asimakopoulos F (2013). MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages. Br J Haematol. 160:779-84. Epub 2012 Dec 18. PMID: 23252623
- McCool KW and Miyamoto S (2012). DNA damage-dependent NF-κB activation: NEMO turns nuclear signaling inside out. Immunol Rev. 246:311-26. Review. PMID: 22435563
- Young EW, Pak C, Kahl BS, Yang DT, Callander NS, Miyamoto S, and Beebe DJ (2012). Microscale functional cytomics for studying hematologic cancers. Blood. 119:e76-85. Epub 2012 Jan 18. PMID: 22262772
- Lee MH, Mabb AM, Gill GB, Yeh ET, and Miyamoto S (2011). NF- ∫B induction of the SUMO protease SENP2: A negative feedback loop to attenuate cell survival response to genotoxic stress. Mol Cell. 43:180-91. PMID: 21777808