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
- Hwang B, McCool K, Wan J, Wuerzberger-Davis SM, Young EW, Choi EY, Cingolani G, Weaver BA, Miyamoto S. IPO3 mediated nonclassical nuclear import of NEMO drives DNA damage-dependent NF-κB activation. J Biol Chem. 2015 Jun 9. pii: jbc.M115.645960.
- Pak C, Callander NS, Young EW, Titz B, Kim K, Saha S, Chng K, Asimakopoulos F, Beebe DJ, Miyamoto S. MicroC(3): an ex vivo microfluidic cis-coculture assay to test chemosensitivity and resistance of patient multiple myeloma cells. Integr Biol. (Camb). 2015 Jun 8;7(6):643-54.
- Jackson SS, Oberley C, Hooper CP, Grindle K, Wuerzberger-Davis S, Wolff J, McCool K, Rui L, Miyamoto S. Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling. Exp Cell Res. 2015 Feb 1;331(1):58-72.
- Hooper C, Jackson SS, Coughlin EE, Coon JJ, Miyamoto S. Covalent modification of the NF-κB essential modulator (NEMO) by a chemical compound can regulate its ubiquitin binding properties in vitro. J Biol Chem. 2014 Nov 28;289(48):33161-74.
- 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