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
- 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
- Wuerzberger-Davis SM and Miyamoto S (2010). TAK-ling IKK activation: "Ub" the judge. Sci Signal. 3:pe3. PMID: 20086238
- McCool K and Miyamoto S (2009). A PAR-SUMOnious mechanism of NEMO activation. Mol Cell. 36:349-50. PMID: 19917242
- Wuerzberger-Davis SM, Nakamura Y, Seufzer BJ, and Miyamoto S (2006). NF-kB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage. Oncogene. 26:641-651. PDF PMID 16862178
- Mabb A, Wuerzberger-Davis SM, and Miyamoto S (2006). PIASy mediates NEMO sumoylation and NF-kB activation in response to genotoxic stress. Nature Cell Biol. 8:986-993. PDF PMID 16906147
- Chang PY and Miyamoto S (2006). NFKB1 is a direct target of the TAL1 oncoprotein in human T leukemia cells. Cancer Res. 66:6008-6013. PDF PMID 16778171
- Chang PY and Miyamoto S (2006). Nuclear factor-kappaB dimer exchange promotes a p21(waf1/cip1) superinduction response in human T leukemic cells. Mol Cancer Res. 4:101-112. PDF PMID 16513841
- Wu Z, Shi Y, Tibbetts RS, and Miyamoto S (2006). Molecular linkage between the kinase ATM and NF-kB signaling in response to genotoxic stimuli. Science 311:1141-1146. PMID 16497931 (Perspective: Bartek J and Lukas J. The stress of finding NEMO. Science. 311:1110-1111.)