This project focuses on studying how proapoptotic Bcl-2 family proteins Bax and Bak regulate apoptosis in response to ER stress, and extends the study to determine how excitotoxic neuronal cell death is regulated using Bax/Bak doubly deficient model system. ER stress triggers the unfolded protein response (UPR), which ultimately results in apoptosis. It remains unclear how signals from ER stress is transduced to initiate apoptosis. Bax and Bak play a fundamental role in initiating apoptosis. Preliminary studies have suggested that in addition to their presence at the mitochondrial outer membrane, Bax and Bak also localize to the ER and initiate apoptosis. The following areas will be addressed to study the mechanisms involved in the initiation of apoptosis by Bax and Bak from the ER: (a) Transcriptional and post-translational regulation of both anti-apoptotic and proapoptotic multi-domain Bcl-2 family proteins and, modification of the BH3-only proteins, e.g., change of localization, phosphorylation, protease cleavage, and transcriptional regulation, in response to ER stress, (b) Involvement of intracellular Ca2+ and proteases that may mediate cell death in response to ER stress, (c) Determining whether Bax/Bak can induce ER leakage by looking at the release of ER lumenal proteins into cytosol.
The second aim i s to characterize excitotoxic neuronal cell death using Bax/Bak doubly deficient cells. Excitotoxic cell death has been implicated in human neurodegenerative diseases and brain tumor invasion. The existence of both apoptotic and necrotic forms of cell death makes it complicated to study the mechanisms involved. Deficiency in both Bax and Bak blocks mitochondrial apoptotic pathways, yet neural progenitor cells isolated from Bax/Bak-deficient mice are sensitive to NMDAand amyloid B (AB)-induced cell death. Thus, mechanisms involved in excitotoxic cell death can be studied in Bax/Bak-deficient cells without the complexity resulting from the death amplification effect of mitochondria. Since excitotoxic cell death shares features with the ER-mediated cell death, such as the perturbation of intracellular Ca2+ homeostasis, I plan to study excitotoxic cell death by: (a) Isolating and culturing cerebellar granule cells and establishing immortalized NPC lines, (b) Characterizing cell death induced by NMDA and Ap in Bax/Bak-deficient cells to determine whether these cells die with characteristic apoptotic or necrotic features, (c) Determining the involvement of the acid-sensitive ionic channels (ASICs) or poly(ADP-ribose) polymerase (PARP) in excitotoxic cell death using Bax/Bak-deficient cells, and study aspartyl and calpain proteases that may be involved in Bax/Bak-independent cell death, (d) Studying the role of intracellular Ca2+ in excitotoxic neuronal cell death.
|Catanzaro, Joseph M; Guerriero, Jennifer L; Liu, Jingxuan et al. (2011) Elevated expression of squamous cell carcinoma antigen (SCCA) is associated with human breast carcinoma. PLoS One 6:e19096|
|Ullman, Erica; Pan, Ji-An; Zong, Wei-Xing (2011) Squamous cell carcinoma antigen 1 promotes caspase-8-mediated apoptosis in response to endoplasmic reticulum stress while inhibiting necrosis induced by lysosomal injury. Mol Cell Biol 31:2902-19|
|Lin, Fubao; Ren, Xiang-Dong; Pan, Zhi et al. (2011) Fibronectin growth factor-binding domains are required for fibroblast survival. J Invest Dermatol 131:84-98|
|Pan, Ji-An; Ullman, Erica; Dou, Zhixun et al. (2011) Inhibition of protein degradation induces apoptosis through a microtubule-associated protein 1 light chain 3-mediated activation of caspase-8 at intracellular membranes. Mol Cell Biol 31:3158-70|
|Dou, Zhixun; Pan, Ji-An; Lin, Richard Z et al. (2011) The beta identity of class I PtdIns3K: A positive role of p110* in autophagy revealed. Autophagy 7:246-7|
|Guerriero, Jennifer L; Ditsworth, Dara; Catanzaro, Joseph M et al. (2011) DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity. J Immunol 186:3517-26|
|Dou, Zhixun; Chattopadhyay, Mohar; Pan, Ji-An et al. (2010) The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy. J Cell Biol 191:827-43|
|Fan, Yongjun; Dickman, Kathleen G; Zong, Wei-Xing (2010) Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition. J Biol Chem 285:7324-33|
|Catanzaro, Joseph; Zong, Wei-Xing (2010) Pinpointing Pin1 in non-small cell lung carcinoma. Cancer Biol Ther 9:120-1|
|Madesh, Muniswamy; Zong, Wei-Xing; Hawkins, Brian J et al. (2009) Execution of superoxide-induced cell death by the proapoptotic Bcl-2-related proteins Bid and Bak. Mol Cell Biol 29:3099-112|
Showing the most recent 10 out of 12 publications