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 tumorigenesis Aim1: 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.
Aim2 : understand the regulation of TNF-induced necrosis. a) Investigate the mechanism of MLKL-mediated necrosis. b) identifying new components of TNF-induced necrosis.
|Zhang, Tiejun; Park, Kyeong Ah; Li, Yuwen et al. (2013) PHF20 regulates NF-ÎºB 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-ÎºB 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-ÎºB 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) TNFÎ± induced noncanonical NF-ÎºB activation is attenuated by RIP1 through stabilization of TRAF2. J Cell Sci 124:647-56|
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