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 cell death in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation, and cell death. 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 and its role in inflammation and cancer development remain unknown. Therefore, uncovering the molecular mechanism of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to understand its role in inflammation and cancer development. In last year, we have made several significant contributions to the understanding of the molecular mechanism regulating TNF signaling and the regulation of cell death. In the future, we will continue to investigate the regulation of TNF signaling, particularly the molecular mechanisms of TNF-induced cell death, and to explore the role of cell death in tumorigenesis as specified in the following: Studying the regulation of TNF-induced cell death and the involvement of key cell death regulatory proteins in tumorigenesisAim1: Investigating the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein, ATIA, and its potential role in tumorigenesis.a)Understanding the underlying mechanism of the anti-apoptotic effect of ATIA.b)Demonstrating the importance of ATIA in tumorigenesis.
Aim 2 : Identifying and studying novel players in TNF-induced necrosis and exploring the role of necrosis in tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC010376-12
Application #
8554052
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2012
Total Cost
$1,115,519
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-κB 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
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Morgan, Michael J; Liu, Zheng-gang (2011) Crosstalk of reactive oxygen species and NF-κB 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) TNFα induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2. J Cell Sci 124:647-56

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