1. 細胞自噬(autophagy)與細胞膜運輸途徑(membrane trafficking)之分子機制。


本實驗室的研究主題在解析控制蛋白質傳遞(protein targeting)的分子之特性,以期深入探討細胞自噬(autophagy)的分子機制。 透過細胞自噬的傳遞,動物細胞的溶小體(lysosome)以及真菌細胞中相對映的濾泡胞器(vacuole)為分解細胞質成分的主要構造之一 ,更是細胞代謝老舊與受損胞器的唯一途徑。近年來研究發現,細胞自噬與生物個體發生過程中,由 細胞分化起乃至於細胞老化死亡間都有密切的關係。

另外,細胞自噬也與病毒及細菌的免疫反應、抑制阿滋海默症等神經退化疾病以及對抗腫瘤細胞生長等人類疾病有關。 因此,研究細胞自噬的分子機制具有基礎科學與醫學應用的貢獻及價值。

過去十餘年間,由酵母菌系統中的研究確立了三十多個ATG基因參與細胞自噬的調控, 而這其中絕大部分的基因又同時控制另一個特殊的細胞膜運輸過程-細胞質至濾泡傳遞途徑 (cytoplasm-to-vacuole targeting pathway),此發現開啟並加速了選擇性細胞自噬的研究。

分析動物細胞的ATG同源基因發現,細胞自噬可能經由選擇性去除受損的蛋白質及胞器,甚至促成細胞死亡, 以避免腫瘤細胞生長或神經組織退化。 本實驗室利用酵母菌模式系統探討控制細胞自噬之分子特性,並將實驗成果用於分析細胞自噬與阿滋海默症等神經退化疾病及腫瘤細胞生長之關係。


The accumulation of protein aggregate in neuronal inclusions is a hallmark of many neurodegenerative diseases, including Huntington’s and Parkinson’s diseases. Although the role of increased autophagy activities in these neuronal cell death is still controversial, intracellular protein aggregate induces autophagosome formation is well documented. Autophagosomes are proposed to segregate protein aggregates and deliver them to lysosomes for elimination. The autophagosome delivery capacity is, however, limited and cell death is usually accompanied with over flooded autophagosomes and lysosomes. Despite that this hypothesis remains to be further proved, it is conceivable that autophagy machinery recognizes and sorts intracellular abnormal materials for elimination. In this regard, the autophagy pathway is not only involved in neurodegenerative disease prevention, but also plays a general role in stress and innate immune responses. Our main interest is to study the molecular mechanisms of autophagy regulation. We have chosen the budding yeast model organism Saccharomyces cerevisiae for deciphering the cargo sorting mechanisms and signaling transduction for selective autophagy pathways. The acquired information will be tested in mammalian systems for neurodegenerative disease control.



期刊論文 Journal
  1. Chang, W.-H., Huang, H.-L., Huang, W.-P., Chen, C.-C., Chen, Y.-J. (2016) Armillaridin induces autophagy-associated cell death in human chronic myelogenous leukemia K562 cells. Tumor Biol., 37: 14291-14300. IF: 2.926, Rank: 104/213x100%=48.8%
  2. Tai, Y.-L-, Tung, L.-H., Lin, Y.-C., Lu, P.-J., Chu, P.-Y., Wang, M.-Y., Huang, W.-P., Chen, K.-C., Lee, H., Shen, T.-L. (2016) Grb7 Protein stability modulated by Pin1 in association with cell cycle progression. PLoS One, 11: e0163617. IF: 3.057, Rank: 14/161x100%=8.7%
  3. Klionsky, D.J. et al., (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12: 1-222. IF: 9.108, Rank: 19/187x100%=10.2%
  4. Ho, Y.-S-, Tsai, W.-H., Lin, F.-C., Huang, W.-P., Lin, L.-C., Wu, S.-M., Liu, Y.-R., Chen, W.-P. (2016) Cardioprotective actions of TGFβRI inhibition through stimulating autocrine/paracrine of Survivin and inhibiting Wnt in cardiac progenitors. Stem Cells, 34: 445-455. IF: 5.902, Rank: 11/63x100%=17.5%
  5. Hung, T.-M., Yuan, R.-H., Huang, W.-P., Chen, Y.-H., Lin, Y.-C., Lin, C.-W., Lai, H.S., Lee, P.-H. (2015) Increased Autophagy Markers Are Associated with Ductular Reaction during the Development of Cirrhosis. Am. J. Pathol., 185: 2454-2467. IF: 4.206, Rank: 11/79x100%=13.9%
  6. Hung, S.-Y., Huang, W.-P., Liou, H.-C., Fu, W.-M. (2015) LC3 overexpression reduces Aβ neurotoxicity through increasing α7nAchR expression and autophagic activity in neurons and mice. Neuropharmacol., 93: 243-251. IF: 4.936, Rank: 19/255x100%=7.6%
  7. Kao, C., Chao, A., Tsai, C.-L., Chuang, W.-C., Huang, W.-P., Chen, G.-C., Lin, C.-Y., Wang, T.-H., Wang, H.-S., Lai, C.-H. (2014) Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation. Cell Death Dis., 5: e1510. IF: 5.378, Rank: 38/187x100%=20.3%
  8. Huang, W.-P., Shintani, T., Xie, Z. (2014) Assays for autophagy I: the Cvt pathway and nonselective autophagy. Methods Mol. Biol., 1163: 153-164.
  9. Huang, Y.-L., Chang, C.-L., Tang, C.-H., Lin, Y.-C., Ju, T.-K., Huang, W.-P.*, and Lee, H.* (2014) Extrinsic sphingosine 1-phosphate activates S1P5 and induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells.Cell. Signal., 26: 611-618. (*Corresponding author) IF: 4.191, Rank: 60/187x100%=32.1%
  10. Tung, Y.-T., Wang, B.-J., Hsu, W.-M., Hu, M.-K., Her, G.-M., Huang, W.-P.*, and Liao, Y.F.* (2014) Presenilin-1 Regulates the Expression of p62 to Govern p62-dependent Tau Degradation. Mol. Neurobiol. , 49: 10-27. (*Corresponding author) IF: 5.397, Rank: 32/256x100%=12.5%
  11. Sangsuriya, P., Huang, J.-Y., Chu, Y.-F., Phiwsaiya, K., Jaengsanong, C., Leekitcharoenphon, P., Senapin, S., Huang, W.-P., Withyachumnarnkul, B., Flegel, T.W., and Lo, C.-F. (2014) Construction and application of a protein interaction map for white spot syndrome virus (WSSV). Mol. Cell. Proteomics, 13: 269-282. IF: 5.912, Rank: 6/77x100%=7.8%
  12. Hung, H.-H, Huang, W.-P., and Pan, C.-Y. (2013) Dopamine- and zinc-induced autophagosome formation facilitates PC12 cell survival. Cell Biol. Toxicol., 29: 415-429. IF: 2.842, Rank: 29/90x100%=32.2%
  13. Hsieh, L.-E., Huang, W.-P., Tang, D.-J., Wang, Y.-T., Chen, C.-T., and Chueh, L.-L. (2013) 3C protein of feline coronavirus inhibits viral replication independently of the autophagy pathway. Res. Vet. Sci., 95: 1241-1247. IF: 1.504, Rank: 31/138x100%=22.5%
  14. Lin, J.-C., Huang, W.-P., Liu, C.-L., Lee, J.-J., Liu, T.-P., Ko, W.-C., Huang, Y.-C., Hsu, M.-L., Wu, C.-H., and Chen, Y.-J. (2013) Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts. Transplantation, 95: 791-800. IF: 3.690, Rank: 15/200x100%=7.5%
  15. Mijaljica, D., Nazarko, T.Y., Brumell, J.H., Huang, W.-P., Komatsu, M., Prescott, M., Simonsen, A., Yamamoto, A., Zhang, H., Klionsky, D.J., and Devenish, R.J. (2012) Receptor protein complexes are in control of autophagy. Autophagy, 8: 1701-1705. IF: 9.108, Rank: 19/187x100%=10.2%
  16. Klionsky, D.J. et al., (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 8: 445-544. IF: 9.108, Rank: 19/187x100%=10.2%
  17. Tung, Y.-T., Wang, B.-J., Hu, M.-K., Lee, H., Huang, W.-P., and Liao, Y.-F. (2012) Autophagy: A double-edged sword in Alzheimer's disease. Journal of Biosciences, 37: 157-165. IF: 1.419, Rank: 42/86x100%=48.8%
  18. Sansuriya, P, Senapin, S, Huang, W.-P., Lo, CF, Flegel, TW. (2011) Co-Interactive DNA-Binding between a Novel, Immunophilin-Like Shrimp Protein and VP15 Nucleocapsid Protein of White Spot Syndrome Virus. PLOS ONE, 6(9): e25420. 09, 2012, DOI: 10.1371/journal.pone.0025420
  19. Huang, WC, Chen, YJ, Li, LY, Wei, YL, Hsu, SC, Tsai, SL, Chiu, PC, Huang, W.-P., Wang, YN, Chen, CH, Chang, WC, Chang, WC, Chen, AJ, Tsai, CH, Hung, MC (2011) Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells. Journal of Biological Chemistry, 286, 23: 20558-20568. 09, 2011. DOI: 10.1074/jbc.M111.240796
  20. Huang, Y.-L., Huang, W.-P., and Lee, H. (2011) Roles of sphingosine 1-phosphate on tumorigenesis. World J. Biol. Chem., 2: 25-34.
  21. Chin, T.-Y., Kao, C.-H., Wang, H.-Y., Huang, W.-P., Ma, K.-H., and Chueh, S.-H. (2010) Inhibition of the mammalian target of rapamycin promotes cyclic AMP-induced differentiation of NG108-15 cells. Autophagy, 6: 1139-1156.
  22. Lu, HH, Kao, SY, Liu, TY, Liu, ST, Huang, W.-P., Chang, KW, Lin, SC. (2010) Areca nut extract induced oxidative stress and upregulated hypoxia inducing factor leading to autophagy in oral cancer cells. Autophage, 6(6): 725-737. 02, 2010.
  23. Tung, YT, Hsu, WM, Lee, H, Huang, W.-P., Liao, YF. (2010) The Evolutionarily Conserved Interaction Between LC3 and p62 Selectively Mediates Autophagy-Dependent Degradation of Mutant Huntingtin. Cellular and Molecular Neurobiology, 30(5): 795-806. 07, 2012. DOI: 10.1007/s10571-010-9507-y
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  25. Ho, K.-H., Chang, H.-E., and Huang, W.-P.* (2009)Mutation at the cargo-receptor binding site of Atg8 also affects its general autophagy regulation function.``, Autophagy, 5:461 -471.
  26. Hung, S.-Y., Huang, W.-P., Liou, H.-C. and Fu, W.-M.,(2009)Autophagy protects neuron from Aβ-induced cytotoxicity.``, Autophagy, 5:502 -510.
  27. Chen, KY; Hsu, TC; Huang, PY; Kang, ST; Lo, CF; Huang, W.-P.; Chen, LL, (2009)Penaeus monodon chitin-binding protein (PmCBP) is involved in white spot syndrome virus (WSSV) infection``, Fish & Shellfish Immunology, 27 , 3 , 460 -465.
  28. Chang, HE; Huang, CH; Chang, CY; Huang, W.-P., (2009)Loading of selective cargo stimulates ATG9 cycling in Saccharomyces cerevisae``, Autophagy, 5 : 895 -896.
  29. Chang CL, Ho MC, Lee PH, Hsu CY, Huang, W.-P., Lee H, (2009)S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells``, Am J Physiol Cell Physiol, 297(2):C451 -C458.
  30. Wang, H.-C., Wang, H.-C., Ko, T.-P., Lee, Y.-M., Leu, J.-H., Ho, C.-H., Huang, W.-P., Lo, C.-F., and Wang, A.H.-J.,(2008)WSSV ICP11 is a multi-functional DNA mimic protein that disrupts nucleosome assembly., PNAS, 108: 20758 -20763.
  31. Lai, S.-L., Chan, T.H., Lin, M.-J., Huang, W.-P., Lou, S.-W. and Lee, S.-J., (2008)Diaphanous-related formin 2 and profilin I are required for gastrulation cell movements., PLoS ONE, 3 , , e3439.
  32. Wang HC, Wang HC, Ko TP, Lee YM, Leu JH, Ho CH, Huang, W.-P., Lo CF, Wang AHJ, (2008)White spot syndrome virus protein ICP11: A histone-binding DNA mimic that disrupts nucleosome assembly, Proceedings of the National Academy of Sciences of the United States of America, 105 , 52 , 20758 -20763.
  33. Klionsky, D.J. et al, (2008)Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes, Autophagy, 4(2):151 -175.
  34. Chang CY, Huang, W.-P.,(2007)Atg19 mediates a dual interaction cargo sorting mechanism in selective autophagy. Mol Biol Cell, 18(3): 919 -929.
  35. Wang HC, Wang GH, Kou CF, Lo CF*, Huang, W.-P.*, (2007)Identification of icp11, the most highly expressed gene of shirmp white spot syndrme virus (WSSV)``, Diseases of Aquatic Organisms, 74(3):179 -189.
  36. Chen LL, Lu LC, Wu WJ, Lo CF, Huang, W.-P., (2007)White spot syndrome virus envelope protein VP53A interacts with Penaeus monodon chitin-binding protein (PmCBP).``, Diseases of Aquatic Organisms , 74:171-178.
  37. Chang, CL, Liao, JJ, Huang, W.-P., Lee, H (2007)Lysophosphatidic acid inhibits serum deprivation-induced autophagy in human prostate cancer PC-3 cells.``, Autophagy, 3(3): 268-270.
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  42. Kim J, Huang, W.-P., Klionsky DJ, (2001)``Membrane recruitment of Aut7p in the autophagy and cytoplasm to vacuole targeting pathways requires Aut1p, Aut2p, and the autophagy conjugation complex.``, J Cell Biol, 152 , , 51 -64.
  43. Wang CW, Kim J, Huang, W.-P., Abeliovich H, Stromhaug PE, Dunn WA, Jr, Klionsky DJ, (2001)``Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways. ``, J Biol Chem, 276 , , 30442 -30451.
  44. Noda T*, Kim J*, Huang, W.-P., Baba M, Tokunaga C, Ohsumi Y, Klionsky DJ, (2000)``Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways.``, J Cell Biol, 148 , , 465 -480.
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  • B01 16910 現代生物學
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  • B01 106C0 03 普通生物學實驗丙
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