Proper execution of cell death ensures normal biological processes, and its dysregulation causes human illness, ranging from cancer to neurodegenerative disorders. Apoptosis is a regulated form of cell death. Impairment of apoptosis is not only central to cancer development but also renders tumors refractory to cytotoxic therapy. Hence, further elucidation of the apoptotic signaling framework will not only help understand how cancer cells escape apoptotic checkpoints but also contribute to the development of rationally designed targeted cancer therapy. The BCL-2 family proteins govern cell death-versus-survival decisions at the mitochondria and can be divided into three subfamilies: (1) multidomain antiapoptotic BCL-2, BCL-XL and MCL-1;(2) multidomain proapoptotic BAX and BAK;and (3) proapoptotic BH3-only molecules (BH3s). BH3s relay upstream apoptotic signals to promote apoptosis by either activating BAX/BAK or inactivating BCL-2/BCL-XL/MCL-1. Genetic loss-of-function studies reveal an essential axis of upstream """"""""activator"""""""" BH3s and downstream BAX/BAK in activating mitochondrion-dependent apoptosis. In response to apoptotic signals, the """"""""activator"""""""" BH3s, including BID, BIM and PUMA, trigger the homo-oligomerization of BAX and BAK to permeabilize mitochondria, leading to the efflux of cytochrome c to the cytosol for caspase activation. We recently discovered a novel mechanism by which BH3s activate BAX/BAK- dependent mitochondrial permeabilization. We propose to elucidate this novel mechanism and reclassify BH3s based on their mechanisms in initiating cell death. Activation of BAX/BAK by BH3s not only triggers APAF-1-mediated caspase activation but also initiates caspase- independent cell death. Further characterization of this novel form of cell death holds promises for the future development of anti-cancer therapeutics that targets cancer cells with defective caspase activation. We are also pursing whether BAX and BAK reside in different protein complexes to differentially regulate caspase-dependent and -independent cell death programs. Overall, our goal is to build a comprehensive proapoptotic BCl-2 signaling network in activating mitochondrion-dependent cell death programs, which offers common ground for therapeutic interventions.
The ability of cancer cells to evade cell death constitutes one of the hallmarks of cancer. Hence, studies of fundamental cell death mechanisms provide unique opportunities for molecularly designed cancer therapeutics. The BCL-2 family proteins are the central regulators of cell death. We propose to investigate the molecular mechanisms by which BCL-2 family proteins regulate cell death with the hope that our study will enable novel targeted therapeutic strategies that specifically trigger cell death in cancer cells.
|Hosoi, Ken-Ichiro; Miyata, Non; Mukai, Satoru et al. (2017) The VDAC2-BAK axis regulates peroxisomal membrane permeability. J Cell Biol 216:709-722|
|Garner, Thomas P; Reyna, Denis E; Priyadarshi, Amit et al. (2016) An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. Mol Cell 64:431|
|Mandal, Tirtha; Shin, Seungjin; Aluvila, Sreevidya et al. (2016) Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore. Sci Rep 6:30763|
|Garner, Thomas P; Reyna, Denis E; Priyadarshi, Amit et al. (2016) An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. Mol Cell 63:485-97|
|Chen, Hui-Chen; Kanai, Masayuki; Inoue-Yamauchi, Akane et al. (2015) An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 17:1270-81|
|Zhang, Ji; Fan, Jing; Venneti, Sriram et al. (2014) Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 56:205-18|
|Liu, Han; Westergard, Todd D; Cashen, Amanda et al. (2014) Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4. Cancer Cell 25:530-42|
|Ren, Decheng; Sun, Juan; Wang, Changzheng et al. (2014) Role of BH3-only molecules Bim and Puma in ?-cell death in Pdx1 deficiency. Diabetes 63:2744-50|
|Bean, Gregory R; Ganesan, Yogesh Tengarai; Dong, Yiyu et al. (2013) PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci Signal 6:ra20|
|Rodriguez, Diego A; Zamorano, Sebastian; Lisbona, Fernanda et al. (2012) BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1?. EMBO J 31:2322-35|
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