Research: The research goal of our laboratory is to understand the molecular mechanism of tumor necrosis factor (TNF) signaling and the regulation of cell death and the role of inflammation in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation, and apoptosis. TNF is also involved in many types of diseases, including cancer. Inappropriate production of TNF plays a critical role in the pathogenesis of both acute and chronic inflammatory diseases such as septic shock, acquired immunodeficiency syndrome (AIDS), and arthritis. The development of anti-TNFalpha therapy is arguably the most significant achievement in the treatment of autoimmune-diseases, such as rheumatoid arthritis and Crohn's disease. Opposing effects of TNF on cancer have been described: a high dose of TNF (acute inflammation) has anti-neoplastic effects, such as direct cytotoxicity on certain types of cancer, while an endogenous low-dose of TNF (chronic inflammation) promotes cancer development. Studies from many laboratories have demonstrated that the diverse TNF-mediated biological responses are achieved through activating multiple signaling pathways (see below). Although much information about TNF signaling has been obtained in recent years, many molecular aspects of TNF signaling remain unknown. Especially, for a given type of cells, we still do not understand how cells choose between life and death after TNF treatment. Therefore, uncovering the molecular mechanism for the regulation of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to maximize the potential of applying or blocking this cytokine in cancer treatment. In the last 5 years, we have made several significant contributions to the understanding of the molecular mechanism for the regulation of TNF signaling. Most recently, we generated tumor necrosis factor receptor 1-associated death domain protein (TRADD) null mice and were able to demonstrate the important role of TRADD in TNF receptor 1 (TNFR1) signaling. In the next 4 years, we will continue to investigate the regulation of TNF signaling, particularly the molecular mechanisms that underlie the life and death decision of cells in response to TNF. Therefore, we will focus our research on the following two areas: 1) studying the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein, ATIA, and its potential role in tumorigenesis;2) investigating the role of TRADD in death receptor signaling and the importance of TRADD-mediated inflammatory responses during tumorigenesis. We believe that these proposed studies will provide new knowledge about the underlying molecular events that determine the outcome of a cell exposed to TNF and other death factors and this may eventually lead to improving the therapeutic value of these death factors. In addition, these studies will shed new light on the tumor-promoting effect of inflammatory responses and may help to develop novel cancer treatments. More recently, we found that ATIA is regulated by HIF-1 and protects cells from hypoxia-induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC010376-11
Application #
8350087
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2011
Total Cost
$1,068,246
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Zhang, Tiejun; Park, Kyeong Ah; Li, Yuwen et al. (2013) PHF20 regulates NF-?B signalling by disrupting recruitment of PP2A to p65. Nat Commun 4:2062
Zhao, Jie; Jitkaew, Siriporn; Cai, Zhenyu et al. (2012) Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A 109:5322-7
Pobezinskaya, Yelena L; Liu, Zhenggang (2012) The role of TRADD in death receptor signaling. Cell Cycle 11:871-6
Pobezinskaya, Yelena L; Choksi, Swati; Morgan, Michael J et al. (2011) The adaptor protein TRADD is essential for TNF-like ligand 1A/death receptor 3 signaling. J Immunol 186:5212-6
Sun, Shao-Cong; Liu, Zheng-Gang (2011) A special issue on NF-?B signaling and function. Cell Res 21:1-2
Huang, Yuefeng; Chen, Liang; Zhou, Yi et al. (2011) UXT-V1 protects cells against TNF-induced apoptosis through modulating complex II formation. Mol Biol Cell 22:1389-97
Morgan, Michael J; Liu, Zheng-gang (2011) Crosstalk of reactive oxygen species and NF-?B signaling. Cell Res 21:103-15
Cao, Xiumei; Pobezinskaya, Yelena L; Morgan, Michael J et al. (2011) The role of TRADD in TRAIL-induced apoptosis and signaling. FASEB J 25:1353-8
Choksi, Swati; Lin, Yong; Pobezinskaya, Yelena et al. (2011) A HIF-1 target, ATIA, protects cells from apoptosis by modulating the mitochondrial thioredoxin, TRX2. Mol Cell 42:597-609
Kim, Joo-Young; Morgan, Michael; Kim, Dong-Gun et al. (2011) TNF? induced noncanonical NF-?B activation is attenuated by RIP1 through stabilization of TRAF2. J Cell Sci 124:647-56

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