Selected Publications

Selected Publications and Highlights

 

1) Molecular mechanisms of apoptosis.

Miura, M., Zhu, H., Rotello, R., Hartwieg, E.A., and Yuan, J. (1993). Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75, 653-660.

Highlight: This was the first demonstration of a mammalian caspase, caspase-1 (termed IL-1 beta-converting enzyme at the time), in mediating apoptosis and the ability of Bcl-2 to suppress apoptosis induced by overexpression of caspase-1. This study provided direct evidence for the functional role of mammalian caspases as homologues of C. elegans Ced-3 and a direct link between an anti-apoptotic member of Bcl-2 family and a caspase in regulating apoptosis of mammalian cells.

Gagliardini, V., Fernandez, P.A., Lee, R.K., Drexler, H.C., Rotello, R.J., Fishman, M.C., and Yuan, J. (1994). Prevention of vertebrate neuronal death by the crmA gene. Science 263, 826-828.

Highlight: This was the first demonstration of the role of neuronal caspases in mediating trophic factor deprivation induced apoptosis and provided the first insight into the molecular mechanism that executes neuronal apoptosis.

Li, H., Zhu, H., Xu, C.J., and Yuan, J. (1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501.

Highlight: This study demonstrated the critical role of BID, after its cleavage by caspase-8, as a signal transducer in mediating mitochondrial damage in response to the activation of death receptors.

Wang, S., Miura, M., Jung, Y.K., Zhu, H., Li, E., and Yuan, J. (1998). Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501-509.

Highlight: This study demonstrated the role of caspase-11 in mediating caspase-1 activation and IL1-beta processing after LPS stimulation and established caspase-11 as an upstream regulator of caspase-1.

Yi, C.H., Pan, H., Seebacher, J., Jang, I.H., Hyberts, S.G., Heffron, G.J., Vander Heiden, M.G., Yang, R., Li, F., Locasale, J.W., et al. (2011). Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell 146, 607-620.

Highlight: This study established an in vitro assay using subtiligase to measure the levels of protein N-terminal acetylation and demonstrated that N-alpha-acetylation is sensitive to metabolic regulation. Furthermore, this study demonstrated that Bcl-xL expression can control the levels of protein N-alpha-acetylation by regulating the levels of acetyl-CoA which provides a Bax/Bak independent mechanism to regulate apoptotic sensitivity.

2) The roles and mechanisms of apoptosis in neurodegeneration.

Friedlander, R.M., Gagliardini, V., Hara, H., Fink, K.B., Li, W., MacDonald, G., Fishman, M.C., Greenberg, A.H., Moskowitz, M.A., and Yuan, J. (1997). Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med 185, 933-940.

Highlight: This study provides the first in vivo evidence for the role of caspases in mediating acute neurological damage.

Sanchez, I., Xu, C.J., Juo, P., Kakizaka, A., Blenis, J., and Yuan, J. (1999). Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22, 623-633.

Highlight: This study demonstrated the ability of oligomerized expanded polyglutamine repeats to mediate the activation of caspase-8 and implicated the role of caspases in Huntington’s disease.

Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B.A., and Yuan, J. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103.

Highlight: This study demonstrated the role of caspase-12 as a mediator of ER stress induced apoptosis and in mediating Abeta induced neuronal cell death.

3) Necroptosis, a regulated necrotic cell death pathway:

Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A., and Yuan, J. (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1, 112-119.

Highlight: Using a cell-based assay that undergoes caspase-independent cell death, Degterev et al. isolated a small molecule inhibitor, termed necrostatin-1 (Nec-1), that can potently inhibit this form of cell death. Degterev et al. found that this form of caspase-independent cell death is distinct from any known cell death pathways and named this pathway "necroptosis".

Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I.L., Korkina, O., Teng, X., Abbott, D., Cuny, G.D., Yuan, C., Wagner, G., Hedrick, S.M.,Gerber, S.A., Lugovskoy A & Yuan, J. (2008). Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4, 313-321.

Highlight: This study identified RIP1 kinase as the target of necrostatin-1, necrostatin-3 and necrostatin-4 and necrostatin-5 and established the critical role of RIP1 kinase in mediating necroptosis.

Hitomi, J., Christofferson, D.E., Ng, A., Yao, J., Degterev, A., Xavier, R.J., and Yuan, J. (2008). Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135,1311-1323.

Highlight: Hitomi et al. screened siRNA library targeting 16873 genes in the human genome for genes involved in mediating necroptosis and identified a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. This study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis.

4) Regulation of autophagy in cancers and neurodegeneration.

Furuya, T., Kim, M., Lipinski, M., Li, J., Kim, D., Lu, T., Shen, Y., Rameh, L., Yankner, B., Tsai, L.H. & Yuan, J. (2010). Negative regulation of Vps34 by Cdk mediated phosphorylation. Mol Cell 38, 500-511.

Highlight: This study explored the control of autophagy and class III PI3 kinase during mitosis and demonstrated that phosphorylation of Vps34 by Cdks negatively regulates its lipid kinase activity. Inhibition of Vps34 during mitosis provides a mechanism for autophagy inhibition during mitosis and also when Cdk5 is activated during neurodegeneration.

Lipinski, M.M., Hoffman, G., Ng, A., Zhou, W., Py, B.F., Hsu, E., Liu, X., Eisenberg, J., Liu, J., Blenis, J., Xavier, R.J. & Yuan, J. (2010a). A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions. Dev Cell 18, 1041-1052.

Highlight: This study conducted a genome-wide siRNA screen for genes that regulate autophagy under normal nutrient conditions and demonstrated that the activation of type III PI3 kinase, but not inhibition of mTORC1, is the common regulator of autophagy under normal nutritional condition.

Lipinski, M.M., Zheng, B., Lu, T., Yan, Z., Py, B.F., Ng, A., Xavier, R.J., Li, C., Yankner, B.A., Scherzer, C.R. & Yuan, J. (2010b). Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc Natl Acad Sci U S A 107, 14164-14169.

Highlight: This study investigated the mechanism that regulate autophagy during aging and Alzheimer’s disease and demonstrated that autophagy is transcriptionally down-regulated during normal aging in the human brain while transcriptionally up-regulation of autophagy in the brains of AD patients.

Liu, J., Xia, H., Kim, M., Xu, L., Li, Y., Zhang, L., Cai, Y., Norberg, H.V., Zhang, T., Furuya, T., Jin, M., Zhu, Z., Wang, H., Yu, J., Hao, Y., Choi, A., Ke, H., Ma, D. & Yuan, J. (2011). Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147, 223-234.

Highlight: This study identified a potent small molecule inhibitor of autophagy named "spautin-1" that promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13. This study also demonstrated the ability of Beclin1 to control the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. This study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.

5) Development of small molecule probes for studying cell death and neurodegeneration.

Degterev, A., Lugovskoy, A., Cardone, M., Mulley, B., Wagner, G., Mitchison, T., and Yuan, J. (2001). Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3, 173-182.

Highlight: Degterev et al. developed a fluorescence polarization based assay for screening small molecules that can inhibit the binding of pro-apoptotic Bcl-2 family member Bak with anti-apoptotic Bcl-2 family member Bcl-xL. This study characterized the interaction of BH3-mimetic small molecules with Bcl-xL using multiple biophysical methods such as surface-enhanced laser desorption/ionization (SELDI) chip, mass spectrometry and NMR analyses as well as multiple cellular assays to reveal the ability of small molecules in targeting the BH3-binding pocket of Bcl-xL.

Boyce, M., Bryant, K.F., Jousse, C., Long, K., Harding, H.P., Scheuner, D., Kaufman, R.J., Ma, D., Coen, D.M., Ron, D. & Yuan, J. (2005). A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307, 935-939.

Highlight: Using a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, Boyce et al. identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha) and the ability of salubrinal to block eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. This study provides a proof-in-principle for the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

Sanchez, I., Mahlke, C., and Yuan, J. (2003). Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373-379.

Highlight: Using azo-dye Congo red which binds preferentially to beta-sheets containing amyloid fibrils and can inhibit oligomerization of expanded polyglutamine repeats, Sanchez et al. demonstrated the principle that inhibiting oligomerization can promote the clearance of expanded polyglutamine repeats in vivo and in vitro, preserve normal cellular protein synthesis and degradation functions and maintain cell viability.