许执恒 研究员
E-msil:zhxu@genetics.ac.cn
个人简介
许执恒，研究员，博士生导师
1999年在美国新泽西Rutgers大学获博士学位。1999-2005在美国哥伦比亚大学神经生物学
和精神病中心做博士后及高级研究助理。2005年9月入选中国科学院遗传发育所“百人计划”。
多种神经退行性疾病，如阿尔茨海默病和帕金森病等，都与中枢神经元的异常凋亡有关。由于许多神经退行性病变的具体病理机制尚不明确，因此了解各类信号传导途径在神经元细胞凋亡中的作用，对于神经退行性病变发生机制的研究，以及此类疾病的预防和治疗都具有深远意义。
c-Jun氨基端激酶(JNK, 又称应激活化蛋白激酶,SAPK) 信号通路属于丝裂原激活蛋白激酶
（MAPK）通路,是细胞凋亡的主要信号转导途径之一并与神经退行性疾病关系密切。JNK信号
通路可被细胞外多种刺激通过MAPKKK-MAPKK- MAPK （JNK）所激活。我们发现了多个在神
经细胞凋亡中起关键作用的基因, 并证实参与JNK 传导通路的各种激酶及支架蛋白, 包括
POSH、JIPs、Rac1/Cdc42、MLKs、MKK4/7 和 JNKs，可通过构成一相互作用的复合体--
PJAC (POSH 和 JIP 相关复合体, 上图)而参与凋亡过程。
最近我们又证实促凋亡刺激可促进内源性PJAC成员如POSH、 JIPs 和 MLKs磷酸化和蛋白稳定性的提高，及激酶（包括MLKs、MKK4/7、和 JNKs）磷酸化和活性的加强。这些蛋白稳定性的提高需要MLKs, MKKs 和JNKs的活性。说明PJAC复合体中各成员间存在某种反馈调节机制（下图）：促凋亡刺激首先通过Rac1/Cdc42, MLKs, 和MKK4/7来部分激活JNKs。
这一亚致命水平的JNKs活化再通过一个自我扩增，正向反馈调节机制，将JPAC成员的蛋白稳定性提高到一个极限水平并完全激活
JNK，进而促进细胞凋亡。
目前的主要研究方向
1) 用分子、生化、细胞和神经生物学为手段研究PJAC蛋白激酶复合体新成员在神经元凋亡信号传导通路中的作用与调节机制，进一步揭示JNK信号传导通路在神经退行性疾病病理过程中的意义。
2) 通过免疫共沉淀、酵母双杂交和生物信息学手段来研究一组与人类神经变性疾病相关的基因和蛋白质,如LRRK2。
3) 建立和利用模式动物研究帕金森病的发病机制。
主要论著目录
Welhelm M, Xu Z., and Greene L. (2007) Proapoptotic Nix activates the JNK pathway by interacting with POSH and mediates
death in a Parkinson disease model. J Biol Chem. 282(2):1288-95.
Tang G, Xu Z, Goldman JE. (2006) Synergistic effects of the SAPK/JNK & the proteasome pathways on GFAP accumulation in
Alexander disease.J Biol Chem. 281(50): 38634-43
Kukekov, N*.,Xu Z.*, and Greene(2006) Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic
activation of JNKs. J Biol Chem. 281(22):15517-24. (* Equal contribution)
Xu Z.*, Sproul A., Wang WY, and Greene L. (2006) SIAH1 Interacts with the Scaffold Protein POSH to Promote JNK Activation and Apoptosis. J Biol Chem. 281(1):303-12. (* Corresponding author)
Xu Z.*, Kukekov, N., and Greene L. (2005) A stability-based self-amplifying feed forward loop mechanism for regulation of the
apoptotic JNK pathway. Mol Cell Biol. 25(22):9949-59. (* Corresponding author)
Xu Z.* and Greene L. (2006) Regulation of the apoptotic JNK pathway. Methods Enzymol 406:479-89. (* Corresponding author)
Zheng S.*, Xu Z.*¨, and Longey J. (2005) Cbl-b/Cbl regulates c-Kit receptor stability through the proteasomal pathway in mast
cells. Blood 105(1):226-32. (* Equal contribution, ¨ Corresponding author).
Hanlon SE, Xu Z, Norris DN, Vershon AK. (2004) Analysis of the meiotic role of the mitochondrial ribosomal proteins Mrps17 and
Mrpl37 in Saccharomyces cerevisiae. Yeast. 21(15):1241-52.
Kim K., Kim B., Xu Z, and Kim S. (2004). Mixed lineage kinase (MLK) 3-activated p38 MAP kinase mediates TGF-Beta-induced
apoptosis in hepatoma cells. J Biol Chem. 279(28):29478-84.
Xu Z., Kukekov N., and Greene LA (2003). POSH (plenty of SH3's) Acts as a Scaffold for a Multiprotein Complex that Mediates
JNK Activation in Apoptotic Death. EMBO J 15; 22(2): 252-61
Xu Z, Maroney AC, Dobrzanski P, Greene LA (2001). The MLK family mediates c-Jun N-terminal kinase activation in neuronal
apoptosis. Mol Cell Biol. 21(14): 4713-24.
Maroney AC, Finn JP, Connors TJ, Durkin JT, Xu Z, Meyer SL, Savage MJ, Greene LA, Scott RW, Vaught JL (2001). Cep-1347
(KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem. 276(27): 25302-8.
Troy CM, Rabacchi SA, Xu Z, Maroney AC, Connors TJ, Shelanski ML, Greene LA (2001). beta-Amyloid-induced neuronal
apoptosis requires c-Jun N-terminal kinase activation. J Neurochem. 77(1):157-64.
Xu Z., and Norris D. (1999). The SFP1 gene product of S. cerevisiae regulates G2/M transitions in the mitotic cell cycle and in
response to DNA damage. Genetics 150(4): 1419-28.
INVITED SPEAKING ENGAGEMENTS
Cell Cycle Meeting, Cold Spring Harbor, NY, (Sep., 1998)
Cephalon Inc. West Chester, PA, (April, 2000)
Cell Death Meeting, Cold Spring Harbor, NY, (Oct., 2000)
Cephalon Inc. West Chester, PA, (Nov., 2001)
School of Life Sciences, Fudan University, Shanghai, China (June, 2002)
Department of Pharmacology and Cancer Institute, UMDNJ New Jersey (Dec., 2002)
Programmed Cell Death Meeting, Cold Spring Harbor, NY, (Sep., 2003)
Department of Surgery, Columbia University, New York, NY (Oct, 2003)
Cephalon Inc. West Chester, PA, (Oct, 2003)
Institute of Genetics and Developmental Biology, Chinese Academy of Science, Beijing, China. (Aug. 2004)
Department of Pharmacology and Physiology, Rochester Medical School, Rochester University, Rochester, New York (Jan 2005)
World DNA Day, Chair (apoptosis section), Dalian, China (April, 2005)
中国细胞生物学年会，武夷山 （2005）
