The NF-?B/Rel family of transcription factors contributes to critical cellular processes, including immune, inflammatory and cell survival responses. As such, NF-?B is implicated in immunity-related diseases, such as autoimmunity, as well as multiple types of human malignancies. Understanding mechanisms of NF-?B regulation will not only expand our knowledge of basic cell signaling processes but also provide potential avenues to prevent and/or treat these human disorders. While a large body of literature over the last two decades describes the critical roles of ubiquitin in regulating NF-?B functions, very little is known about regulation of NF-?B signaling by SUMO (small ubiquitin-like modifier), another posttranslational modifier. The long-term goal of this project is to greatly expand our understanding of the mechanisms of NF-?B and SUMO regulation in specific physiological and pathological processes. We have recently uncovered a novel signaling role for SUMOylation of NEMO (NF-?B essential modulator) in NF-?B signaling. Our preliminary data indicate that there exist significant, novel crosstalk mechanisms between the SUMO and NF-?B pathways. Thus, in this proposal, we will test the hypothesis that crosstalk between SUMO and NF-?B signaling systems plays critical roles in regulating certain physiological and pathological processes. This research is expected to considerably expand our knowledge of the molecular links between SUMO and NF-?B pathways and their roles in specific physiological and pathological processes. This research will also generate novel reagents and tools to allow other researchers to investigate SUMO and NF-?B signaling systems in similar and different experimental models. Finally, it may also identify rational targets for drug development against human disorders, such as autoimmunity and specific types of malignancies.

Public Health Relevance

The regulation of cancer cell death is a complex process involving many different molecular pathways. This research seeks to understand the relationships between protein modification by SUMO (Small Ubiquitin-like Modifier) and NF-?B signaling, one of the major cell death-regulatory pathways. This study will significantly expand our understanding of the regulatory mechanisms for normal and cancer cell death signaling, and may also provide rationale targets for the development of new anticancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM083681-03
Application #
8308474
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Maas, Stefan
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$286,679
Indirect Cost
$93,629
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Jackson, Shawn S; Oberley, Christopher; Hooper, Christopher P et al. (2015) Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling. Exp Cell Res 331:58-72
Hwang, Byounghoon; McCool, Kevin; Wan, Jun et al. (2015) IPO3-mediated Nonclassical Nuclear Import of NF-κB Essential Modulator (NEMO) Drives DNA Damage-dependent NF-κB Activation. J Biol Chem 290:17967-84
Hwang, Byounghoon; Phan, Funita P; McCool, Kevin et al. (2015) Quantification of cellular NEMO content and its impact on NF-κB activation by genotoxic stress. PLoS One 10:e0116374
Helzer, Kyle T; Hooper, Christopher; Miyamoto, Shigeki et al. (2015) Ubiquitylation of nuclear receptors: new linkages and therapeutic implications. J Mol Endocrinol 54:R151-67
Jackson, Shawn S; Miyamoto, Shigeki (2015) Dissecting NF-κB signaling induced by genotoxic agents via genetic complementation of NEMO-deficient 1.3E2 cells. Methods Mol Biol 1280:197-215
Shin, Eun Myoung; Hay, Hui Sin; Lee, Moon Hee et al. (2014) DEAD-box helicase DP103 defines metastatic potential of human breast cancers. J Clin Invest 124:3807-24
Hooper, Christopher; Jackson, Shawn S; Coughlin, Emma E et al. (2014) Covalent modification of the NF-κB essential modulator (NEMO) by a chemical compound can regulate its ubiquitin binding properties in vitro. J Biol Chem 289:33161-74
Berry, Scott M; Chin, Emily N; Jackson, Shawn S et al. (2014) Weak protein-protein interactions revealed by immiscible filtration assisted by surface tension. Anal Biochem 447:133-40
Jackson, Shawn S; Coughlin, Emma E; Coon, Joshua J et al. (2013) Identifying post-translational modifications of NEMO by tandem mass spectrometry after high affinity purification. Protein Expr Purif 92:48-53
Mulero, María Carmen; Ferres-Marco, Dolors; Islam, Abul et al. (2013) Chromatin-bound IκBα regulates a subset of polycomb target genes in differentiation and cancer. Cancer Cell 24:151-66

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