Faculty: Shigeki Miyamoto
|Training Areas:||Molecular & Cellular Pharmacology|
Cellular & Molecular Biology
Hematology Training Program
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
- 1997 - Shaw Scientist Award
- H.I. Romnes Faculty Fellow
Other Positions & Affiliations
- Not available
- Hebron E, Hope C, Kim J, Jensen JL, Flanagan C, Bhatia N, Maroulakou I, Mitsiades C, Miyamoto S, Callander N, Hematti P, Asimakopoulos F. MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages. Br J Haematol. 2013 Mar;160(6):779-84. doi: 10.1111/bjh.12175. Epub 2012 Dec 18. PMID: 23252623
- McCool KW, Miyamoto S. DNA damage-dependent NF-κB activation: NEMO turns nuclear signaling inside out. Immunol Rev. 2012 Mar;246(1):311-26. doi: 10.1111/j.1600-065X.2012.01101.x. Review. PMID: 22435563
- Young EW, Pak C, Kahl BS, Yang DT, Callander NS, Miyamoto S, Beebe DJ. Microscale functional cytomics for studying hematologic cancers. Blood. 2012 Mar 8;119(10):e76-85. doi: 10.1182/blood-2011-10-384347. Epub 2012 Jan 18. PMID: 22262772
- Lee MH, Mabb AM, Gill GB, Yeh ET, 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(2):180-91. PMID: 21777808
- Wuerzberger-Davis SM, Miyamoto S (2010). TAK-ling IKK activation: "Ub" the judge. Sci Signal. 3(105):pe3. PMID: 20086238
- McCool K, Miyamoto S (2009). A PAR-SUMOnious mechanism of NEMO activation. Mol Cell.36(3):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.)