Faculty: Shigeki Miyamoto

Dept:	Professor, Oncology
Contact:	6159 WIMR 608-262-9281 smiyamot@wisc.edu
Training Areas:	Molecular & Cellular Pharmacology Cellular & Molecular Biology Molecular Biosciences Cancer Biology MD/PhD Program Hematology Training Program

Research Interests

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

Selected Publications

(Find publications on PubMed)

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.)
Wu Z, Mabb A, and Miyamoto S. (2005). PIDD: a switch hitter. Cell. 123:980-982. PDF PMID 16360026
Berchtold CM, Chen K-S, Miyamoto S, and Gould MN. (2005). Perillyl alcohol inhibits a calcium-dependent constitutive NF-kB pathway. Cancer Res. 65:8558-8566. PDF PMID 16166337
Wuerzberger-Davis SM, Chang P-Y, Berchtold C, and Miyamoto S. (2005). Enhanced G2/M arrest by NF-kB-dependent p21waf1/cip1 induction. Mol Cancer Res. 3:345-353. PDF PMID 15972853
O'Connor S and Miyamoto S. (2005). Evidence for a phosphorylation-independent role for Ser 32 and 36 in proteasome inhibitor resistant (PIR) IkBa degradation. Exp Cell Res. 307:15-25. PDF PMID 15922723
O'Connor S, Shumway S, and Miyamoto S. (2005). Inhibition of IkBa nuclear export as an approach to abrogate NF-kB dependent cancer cell survival. Mol Cancer Res. 3:42-49. PDF PMID 15671248
Miyamoto S. (2004). RelA life and death decisions. Mol Cell. 13:763-764. PDF PMID 15053867
Bates P and Miyamoto S. (2004) Expanded nuclear roles for IkB's. Science STKE 254:48. PMID 15479861
O'Connor S, Shumway SD, and Miyamoto S. (2004). Regulation of constitutive p50/c-Rel activity via proteasome inhibitor-resistant IkBa degradation in B cells. Mol Cell Biol. 24:4895-4908. PDF PMID 15143182
Huang TT, Davis SM, Wu Z, and Miyamoto S. (2003). Sequential modification of NEMO/IKKg by SUMO-1 and ubiquitin mediates NF-kB activation by nuclear DNA damage. Cell. 115:565-576. PMID: 14651848 (News and Views: Hay RT. (2004). Modifying NEMO. Nature Cell Biol. 6:89-91.