哈佛牛人---袁钧英

Junying Yuan, Ph.D.

Professor of Cell Biology





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Department of Cell Biology

Harvard Medical School

240 Longwood Avenue

Boston, MA 02115 Office: 617 432-4170

Assistant: 617 432-4187

Lab: 617 432-4171, -4172,

-4173, -4188, -4195, -4196.

Fax: 617 432-4177

E-mail: jyuan@hms.harvard.edu



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Junying Yuan received her Ph.D. in Neuroscience from Harvard University in 1989 and her undergraduate degree from Fudan University, Shanghai, China, in 1982. Dr. Yuan carried out her postdoctoral research at the Massachusetts Institute of Technology. She was first appointed as Assistant Professor at Harvard Medical School in 1992, when she became a Principal Investigator of the Cardiovascular Research Center at Massachusetts General Hospital. She joined the Department of Cell Biology in 1996 and was appointed a Professor of Cell Biology at Harvard Medical School in 2000.  

Research



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Apoptosis is a genetically regulated cellular suicide mechanism that plays a crucial role in development and in the defense of homeostasis.  The proteins in the Bcl-2 and caspase families play key roles in regulating signal transduction of apoptosis.  We are using cellular, biochemical, genetic and chemical genetic approaches to dissect apoptosis pathways.  The experiments include dissecting the pathway of unfolded protein response, the mechanism of caspase-12 activation, the mechanism of cell death in neuronal degenerative diseases and caspases in apoptosis induced by tumor suppressor gene products.    

Cellular and genetic analyses of caspase functions.  Our work demonstrated a critical role of caspase-8 in polyglutamine repeat induced cell death.  Huntington and related neuronal degenerative diseases are caused by expansion of polyglutamine repeats in the corresponding genetic loci.  In a cellular model of polyglutamine repeat induced cell death, we showed that polyglutamine repeats specifically recruit and activate caspase-8 that is required for cell death in this system.  Our work suggests that recruitment of caspases by mutant proteins may underlie the genetic basis of neuronal degenerative diseases.



Caspase-11 is an upstream caspase which we have shown previously required for activation of caspase-1 and pro-IL-1ß processing.  While the expression of caspase-11 is undetectable in most tissues of healthy mice, it can be induced by a variety of pathological signals.  Caspase-11-deficient mice showed a defect in processing pro-IL-1ß as well as reduced number of apoptotic cells and a defect in caspase-3 activation. We concluded that caspase-11 is an upstream caspase in mediating cytokine secretion as well as apoptosis under brain ischemia and systemic inflammation.



Unfolded protein response in endoplasmic reticulum has been implicated in mediating neuronal cell death in Alzheimer’s disease.  We found that caspase-12 is localized in ER and a deficiency in caspase-12 renders cortical neurons specifically resistant to amyloid ß protein toxicity.  Our work demonstrated a novel ER-specific apoptosis pathway.  



Chemical genetic approaches to dissect the mechanism of Bcl-2.  Heterodimerization of pro- and anti-apoptotic members of the Bcl-2 family through their BH3 domains is critical for regulating cell survival.  To further characterize the role of BH3 domain interaction and develop prototypic small molecule inhibitors of Bcl-2 family, we developed a high throughput screen for Bcl-2 inhibitors.  We isolated two series of Bcl-2 inhibitors and demonstrated by in vivo and in vitro experiments that they induce apoptosis through inhibiting BH3 domain interaction.  Similar chemical genetic approaches are being used in the laboratory to dissect other pathways involved in regulating physiological and pathological cell death.









Selected Original Reports



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(1) Miura M, Zhu H, Hartwieg EA, Rotello R, Yuan J.  Induction of apoptosis in fibroblasts by interleukin-1ß converting enzyme, a mammalian homolog of C. elegans cell death gene ced-3.  Cell 1993; 75: 653-660



(2) Gagliardini V, Fernandez PA, Lee RKK, Drexler HCA, Rotello R, Fishman M, Yuan J.  revention of vertebrate neuronal death by the crmA gene.   Science 1994; 263: 826-828.



(3) Wang L, Miura M, Bergeron L, Zhu H, Yuan J.  Ich-1, an Ice/Ced-3 related gene, encodes both positive and negative regulators of programmed cell death. Cell 1994; 78:739-750.



(5) Friedlander RM, Gagliardini V, Wang J, Brown RH, Yuan J. Inhibition of ICE slows ALS in mice.  Nature. 1997; 388: 31.



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



(8) Bergeron L, Perez GI, MacDonald G, Shi L, Sun Y, Jurisicova| A, Varmuza S, Latham KE, Flaws JA, Salter J, Hara H, Moskowitz MA, Li E, Greenberg A, Tilly JL, Yuan J. Defects in regulation of apoptosis in caspase-2-deficient mice.  Genes & Dev. 1998; 12:1304-1314.



(9) Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA.  Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J. Neurosci. 1998; 18: 3659-3668



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



(11) Chou JJ, Li H, Salveson G, Yuan J and Wagner G. Solution structure of Bid, an intracellular amplifier of apoptosis. Cell. 1999; 96:615-624.



(12)Sánchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, and Yuan J. Caspase-8 is Required for Cell Death Induced by Expanded Polyglutamine Repeats. Neuron. 1999; 22: 623-633.



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



(14) Kang, S-J., Wang, S., Hara, H., Peterson, E. P., Srinivasan, A., Namura, S., Amin-Hanjani, S., Tomaselli, K. J., Thornberry, N. J., Moskowitz, M. A., and Yuan, J.  Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 2000. 149, 613-622.



(15) Nakagawa T and Yuan J. Cross-talk between two cysteine protease families: activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 2000. 150(4):887-894.



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









Selected Reviews, Chapters and Editorials



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(1) Cryns VL and Yuan J.  roteases to die for.  Gen. & Dev. 1998; 12: 1551-1570.

(2) Yuan J. and Yankner B.  Apoptosis in Nervous System. 2000. Nature. 407, 802-809.













Personnel



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Assistant

Gentiana Pambuku - gentiana_pambuku@hms.harvard.edu , ph. - 617-432-4187



Graduate students



Mike Boyce

Shin-Jung Kang

Kevin Welch



Postdoctoral fellows



Sungkwan An

Alexei Degterev

Roger Greenberg

Toshiyuki Nakagawa

Roberto Sanchez-Olea

Yasuhito Terui

Jianhua Yao

Lina Yoo



Instructors



Ivelisse Sanchez

Or Gazoni



Lab manager



Hong Zhu



Research Assistants



Odmara Barreto-Chang

Christopher Bozzuto

Christian Mahlke

Junying Yuan

Harvard Medical School

Telephone: 617- 432-4170

Email: jyuan@hms.harvard.edu

Predocs: 5 Postdocs: 11 Completed PhD’s: 2

Apoptosis is a genetically regulated cellular suicide mechanism that plays a crucial role in development and in defense of tissue homeostasis. The members of Bcl-2, caspases families and Apaf-1 related molecules play central roles in regulating apoptosis. The recent work in our lab centers on the upstream signal transduction pathways that regulate apoptotic pathways with an emphasis on neurodegeneration. We are studying the receiving mechanisms by which cells sense cytotoxic stimuli, the signal transduction pathways that translate and amplify the cyotoxic signal and the downstream mechanisms that turn on the execution machinery in cells.



Caspases are key proteases involved in signaling and execution of apoptosis. We have identified two caspases, caspases-11 and caspases-12, that are relevant to pathological neuronal cell death. Caspase-11 is inducible by a variety of pathological stimuli and involved in regulating pathological cell death and pro-inflammatory cytokine release. Caspase-12 mediates an endoplasmic reticulum specific apoptotic pathway under ER stress condition. We are studying their mechanisms of activation and their roles in regulating patho-physiological responses, particularly in neural degenerative diseases such as Alzheimer’s disease.



We are studying the mechanisms of neuronal cell death in Parkinson’s disease, Huntington’s disease and Alzheimer’s disease. We are dissecting the molecular mechanims by which -synuclein functions normally and pathological mechanism by which it participates in neuronal degeneration. We are studying the mechanism by which expanded polyglutamine repeats induces neuronal cell death by molecular and chemical genetic methods. We are also studying the roles of caspases in regulating processing of key molecules involved in Alzheimer’s disease such as APP.



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



Bergeron L, Perez GI, MacDonald G, Shi L, Sun Y, Jurisicova| A, Varmuza S, Latham KE, Flaws JA, Salter J, Hara H, Moskowitz MA, Li E, Greenberg A, Tilly JL, Yuan J. (1998) Defects in regulation of apoptosis in caspase-2-deficient mice. Genes & Dev. 12, 1304-1314.



Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA. (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J. Neurosci. 18, 3659-3668.



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.



Sánchez I, Xu CJ, 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.


 



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