專家信息 科學(xué)研究 論文專著 榮譽(yù)獎(jiǎng)勵(lì) 媒體報(bào)道

      專家信息:


      張曉坤,男,1963年2月出生,博士,F(xiàn)任廈門大學(xué)藥學(xué)院院長,教授、博士生導(dǎo)師。國家特聘專家,教育部長江學(xué)者講座教授,中組部第一批“千人計(jì)劃”特聘教授,福建省引進(jìn)高層次創(chuàng)業(yè)創(chuàng)新人才,兼任美國加利福尼亞州Sanford-Burnham醫(yī)學(xué)研究所教授,中國科學(xué)院上海生命科學(xué)研究院客座教授。

      教育及工作經(jīng)歷:

      1982年畢業(yè)于廈門大學(xué)生物學(xué)系。

      1982年至1984年任廈門大學(xué)生物系研究助理。

      1989年獲美國佛蒙特州大學(xué)生物化學(xué)博士學(xué)位。

      1989年至1992年 美國加利福尼亞州Burnham學(xué)院跟隨Magnus Pfahl博士開展博士后的工作。

      1992年至1993年在美國加利福尼亞州拉霍亞Burnham學(xué)院任研究助理。

      1993年在美國加利福尼亞州拉霍亞Burnham學(xué)院組建自己的實(shí)驗(yàn)室,任助理教授。

      1999年至2005年在美國加利福尼亞州拉霍亞Burnham學(xué)院任副教授。

      2006年升任教授。

      2006年在廈門大學(xué)生物醫(yī)學(xué)研究院工作。

      社會任職:

      資料更新中……

      教學(xué)情況:

      主講課程:

      資料更新中……

      培養(yǎng)研究生情況:

      資料更新中……

      科學(xué)研究:


      研究方向:

      主要從事核受體的基礎(chǔ)研究和應(yīng)用。

      承擔(dān)科研項(xiàng)目情況:

      資料更新中……

      科研成果:

      1. 發(fā)現(xiàn)RXR通過調(diào)控它的雙鏈活性調(diào)控靶基因的轉(zhuǎn)錄(Nature 355:441-446,1992),這是他在這一領(lǐng)域最先報(bào)道,該文章在1994年的Nature雜志上被評為熱點(diǎn)文章,本發(fā)現(xiàn)促使RXR功能研究領(lǐng)域進(jìn)入飛躍式的發(fā)展時(shí)期;

      2. 發(fā)現(xiàn)視黃醇新的作用、腫瘤耐藥的分子機(jī)制(Nature 340: 653, 1989),最先發(fā)現(xiàn)視黃醇調(diào)控RXR同源二聚體活性的新的信號轉(zhuǎn)導(dǎo)通路(Nature 358: 587-591, 1992),開辟了基于RXR活性調(diào)控發(fā)現(xiàn)和發(fā)展新的癌癥治療藥物的時(shí)期;

      3. 發(fā)現(xiàn)某些視黃醇物質(zhì)和凋亡誘導(dǎo)劑可通過調(diào)控TR3出核,使TR3從一個(gè)細(xì)胞生長的關(guān)鍵介導(dǎo)分子轉(zhuǎn)變?yōu)榉浅S杏们暗蛲龇肿樱⊿cience 289: 1159-1164, 2000),使核受體研究以及基于新的作用機(jī)制的理解發(fā)現(xiàn)和發(fā)展新的藥物進(jìn)入另一個(gè)嶄新的時(shí)期;

      4. 2004年的另一個(gè)重大發(fā)現(xiàn)是,發(fā)現(xiàn)了通過調(diào)控Bcl-2 N-末端環(huán)區(qū)的活性,可使Bcl-2從一個(gè)抗凋亡分子轉(zhuǎn)變?yōu)榍暗蛲龇肿,其中包括TR3的作用(Cell 116:527-40,2004)。對于人類約一半的惡性腫瘤過表達(dá)Bcl-2并由于該基因的表達(dá)使大量化療藥物失去作用而言,該發(fā)現(xiàn)具有重大的意義;

      5. 發(fā)現(xiàn)和發(fā)展了基于核受體調(diào)控的許多非常有效的化合物,在基礎(chǔ)研究中發(fā)揮了巨大的作用,其中有自己的專利藥物Targretin已在臨床上用于皮膚癌的治療,這是世界上第一個(gè)以RXRa為分子靶點(diǎn)的藥物,開創(chuàng)了由分子作用機(jī)理理性開發(fā)藥物的新的時(shí)期。

      發(fā)明專利:

      國外

      1. Heterodimers of retinoid X receptors(RXRs)and other steroid hormone receptors,發(fā)明專利,2006年04月,美國,等級:1。

      2. Cytoplasmic Activity of Retinoid X Receptor and its Regulation by Ligands and Dimerization,發(fā)明專利,2005年03月,美國,等級:1。

      3. Induction of Apoptosis in cancer cells,發(fā)明專利,2006年05月,美國,等級:1。

      4. Conversion of Apoptotic proteins,發(fā)明專利,2006年02月,美國,等級:1。

      國內(nèi)

      1. 紫草素衍生物的應(yīng)用 曾錦章; 張曉坤; 劉婕; 李紹順; 周文; 王光輝 【中國專利】廈門大學(xué) 2010-03-31

      2. 皂苷類化合物及其應(yīng)用 陳海峰; 區(qū)文超; 劉世明; 孫翠玲; 姚新生; 張曉坤 【中國專利】廈門大學(xué); 廣州醫(yī)學(xué)院第二附屬醫(yī)院 2010-07-14

      3. 一種生物堿的抗癌應(yīng)用 曾錦章; 張曉坤; 韋楊燁 【中國專利】廈門大學(xué) 2011-01-19

      4. 一種具有抗血小板活化、聚集及炎癥作用的化合物及其制備方法和用途 區(qū)文超; 劉世明; 陳海峰; 劉東萍; 姚新生; 張曉坤 【中國專利】廣州醫(yī)學(xué)院第二附屬醫(yī)院; 廈門大學(xué) 2011-07-13

      5. 一種倍半萜的抗癌應(yīng)用 曾錦章; 張曉坤; 陳鯉群; 林文翰 【中國專利】廈門大學(xué) 2011-07-06

      論文專著:


      在《自然》、《科學(xué)》及《細(xì)胞》等國際核心期刊發(fā)表具有重要?jiǎng)?chuàng)見的核激素受體研究論文130余篇。

      出版專著:

      資料更新中……

      發(fā)表英文論文:

      1. Zhang, X-k., Huang, D.P., Chiu, D.K., and Chiu, J.F. The expression of oncogenes in human developing liver and hepatomas. Biochem. Biophys. Res. Comm. 142: 932-938. 1987.

      2. Zhang, X-k., Wang, Z., Lee, A., Huang, D.P., and Chiu, J.F. Differential expression of cellular oncogenes during rat liver development. Cancer Lett. 41: 147-155. 1988.

      3. Li, P.M., Zhong, J.L., Chen, R.Q., Zhang, X-k., Ho, K.L., Chiu, J.F., and Huang, D.P. Zhi-mu saponin inhibits alpha-fetoprotein gene expression in developing rat liver. Int. J. Biochem. 21: 15-22. 1989.

      4. Graupner, G., Wills, K.N., Tzukerman, M., Zhang, X-k., and Pfahl, M. Dual regulatory role for thyroid-hormone receptors allows control of retinoic acid receptor activity. Nature (London) 340: 653-656. 1989.

      5. Zhang, X-k., Huang, D.P., Qiu, D.K., and Chiu, J.F. The expression of c-myc and c-N-ras in human cirrhotic livers, hepatocellular carcinomas and liver tissue surrounding the tumors. Oncogene 5: 909-914. 1990.

      6. Hoffmann, B., Lehmann, J.M., Zhang, X-k., Hermann, T., Graupner, G., and Pfahl, M. A retinoic acid receptor-specific element controls the retinoic acid receptor- promoter. Mol. Endocrinol. 4: 1727-1736. 1990.

      7. Tzukerman, M., Zhang, X-k., Hermann, T., Wills, K.N., Graupner, G., and Pfahl, M. The human estrogen receptor has transcriptional activator and repressor functions in the absence of ligand. New Biol. 2: 613-620. 1990.

      8. Pfahl, M., Tzukerman, M., Zhang, X-k., Lehmann, J.M., Hermann, T., Wills, K.N., and Graupner, G. Nuclear retinoic acid receptors: cloning, analysis, and function. Methods Enzymol. 189: 256-270. 1990.

      9. Zhang, X-k., Zucker, M.I., Huang, D.P., Lin, T-S., Prusoff, W.H., and Chiu, J.F. Alteration of cellular oncogene expression in L1210 cells by a nitrosourea alalog of thymidine. Cancer Comm. 3: 119-126. 1991.

      10. Zhang, X-k., Dong, J.M., and Chiu, J.F. Regulation of -fetoprotein gene expression by antagonism between AP-1 and the glucocorticoid receptor at their overlapping binding site. J. Biol. Chem. 266: 8248-8254. 1991.

      11. Graupner, G., Zhang, X-k., Tzukerman, M., Wills, K.N., Hermann, T., and Pfahl, M. Thyroid hormone receptors repress estrogen receptor activation of a TRE. Mol. Endocrinol. 5: 365-372. 1991.

      12. Hermann, T., Zhang, X-k., Tzukerman, M., Wills, K.N., Graupner, G., and Pfahl, M. Regulatory functions of a non-ligand-binding thyroid hormone receptor isoform. Cell Regul. 2: 565-574. 1991.

      13. Pfahl, M., Zhang, X-k., Lehmann, J.M., Husmann, M., Graupner, G., and Hoffmann, B. Molecular mechanisms of retinoic acid action. In G. Morriss-Kay (ed.), Retinoids in normal development and teratogenesis. Oxford University Press, Oxford. p. 51-64. 1992.

      14. Zhang, X-k., Wills, K.N., Graupner, G., Tzukerman, M., Hermann, T., and Pfahl, M. Ligand-binding domain of thyroid hormone receptors modulates DNA binding and determines their bifunctional roles. New Biol. 3: 169-181. 1991.

      15. Wills, K.N., Zhang, X-k., and Pfahl, M. Coordinate expression of functionally distinct thyroid hormone receptor  isoforms during neonatal brain development. Mol. Endocrinol. 5: 1109-1119. 1991.

      16. Tzukerman, M., Zhang, X-k., and Pfahl, M. Inhibition of estrogen receptor activity by the tumor promoter 12-O-tetradeconylphorbol-13-acetate: a molecular analysis. Mol. Endocrinol. 5: 1983-1992. 1991.

      17. Yang-Yen, H-F*., Zhang, X-k.*, Graupner, G., Tzukerman, M., Sakamoto, B., Karin, M, and Pfahl, M. Antagonism between retinoic acid receptors and AP-1: implications for tumor promotion and inflammation. New. Biol. 3: 1206-1219. 1991. *Equal contribution.

      18. Zhang, X-k., Tran, P.B., and Pfahl, M. DNA binding and dimerization determinants for thyroid hormone receptor  and its interaction with a nuclear protein. Mol. Endocrinol. 5: 1909-1920. 1991.

      19. Zhang, X-k., Wills, K.N., Husmann, M., Hermann, T., and Pfahl, M. Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities. Mol. Cell. Biol. 11: 6016-6025. 1991.

      20. Zhang, X-k., Hoffmann, B., Tran, P., Graupner, G., and Pfahl, M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature (London) 355: 441-446. 1992.

      21. Lehmann, J.M., Zhang, X-k., and Pfahl, M. RAR2 expression is regulated through a retinoic acid response element embedded in SP1 sites. Mol. Cell. Biol. 12: 2976-2985. 1992.

      22. Hermann, T., Hoffmann, B., Zhang, X-k., Tran, P., and Pfahl, M. Heterodimeric receptor complexes determine 3,5,3'-triiodothyronine and retinoid signaling specificities. Mol. Endocrinol. 6: 1153-1162. 1992.

      23. Zhang, X-k., Egan, J.O., Huang, D-p., Sun, Z.L., Chien, V.K., and Chiu, J.F. Hepatitis B virus DNA integration and expression of an erbB-like gene in human hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 188: 344-351. 1992.

      24. Tran, P., Zhang, X-k., Salbert, G., Hermann, T., Lehmann, J.M., and Pfahl, M. COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol. Cell. Biol. 12: 4666-4676. 1992.

      25. Zhang, X-k., Lehmann, J.M., Hoffmann, B., Dawson, M., Cameron, J., Graupner, G., Hermann, T., Tran, P., and Pfahl, M. Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature (London) 358: 587-591. 1992.

      26. Hermann, T., Hoffmann, B., Piedrafita, F.J., Zhang, X-k., and Pfahl, M. V-erb A requires auxiliary proteins for dominant negative activity. Oncogene. 8: 55-65. 1993.

      27. Zhang, X-k. and Pfahl, M. Regulation of retinoid and thyroid hormone action through homodimeric and heterodimeric receptors. Trends Endocrinol. Metab. 4: 156-162. 1993.

      28. Lehmann, J.M., Zhang, X-k., Graupner, G., Lee, M.O., Hermann, T., Hoffmann, B., and Pfahl, M. Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching. Mol. Cell. Biol. 13: 7698-7707. 1993.

      29. Zhang, X-k. and Pfahl, M. Hetero- and homodimeric receptors in thyroid hormone and vitamin A action. Receptor. 3: 183-191. 1993.

      30. Zhang, X-k. and Pfahl, M. Molecular mechanisms of action for vitamin-A derived hormones in receptor-mediated biological processes. Implications for Evaluating Carcinogens. (ed. T.J. Slaga). Wiley-Liss Press. 1993.

      31. Zhang, X-k., Salbert, G., Lee, M-O., and Pfahl, M. Mutations that alter ligand-induced switches and dimerization activities in the retinoid X receptor. Mol. Cell. Biol. 14: 4311-4323. 1994.

      32. Pfahl, M., Apfel, R., Bendik, I., Fanjul, A., Graupner, G., Lee, M-O., La-Vista, N., Lu, X-P, Piedrafita, J., Ortiz-Caseda, A., Salbert, G., and Zhang, X-k. Nuclear retinoid receptors and their mechanism of action. Vitamins and hormones. (ed. Gerald Litwac). Vol. 49, pp. 327-382. 1994.

      33. Lee, M-O., Hobbs, P.D., Zhang, X-k., Dawson, M.I., and Pfahl, M. A synthetic retinoid antagonist inhibits the human immunodeficiency virus type 1 promoter. Proc. Nat. Acad. Sci. 91: 5632-5636. 1994

      34. Zhang, X-k., Liu, Y., Lee, M-O., and Pfahl, M. A specific defect in the retinoic acid response associated with human lung cancer cell lines. Cancer Res. 54: 5663-5669. 1994.

      35. Zhang, X-k. Molecular mechanisms of action for vitamin A-derived hormones. Prog. Clin. Biol. Res. 387: 59-71. 1994.

      36. Lee, M-O., Liu, Y., and Zhang, X-k. A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensibility in transcriptional activation of the lactoferrin gene. Mol. Cell. Biol. 15: 4194-4207. 1995.

      37. Alam, M., Zhestkov, V., Sani, B.P., Venepally, P., Levin, A.A., Kazmer, S., Li, E., Norris, A.W., Zhang, X-k., Lee, M.-O., Hill, D.L., Lin, T.-H., Brouillette, and Muccio, D.D. Conformationally defined 6-s-trans retinoic acid analogs. 2: Selective agonists for nuclear receptor binding and transactivational activity. J. Med. Chem. 38: 2302-2310. 1995.

      38. Dawson, M.I., Chao, W-R., Pine, P., Jong, L., Hobbs, P.D., Rudd, C., Quick, T.C., Niles, R.M., Zhang, X-k., Lombardo, A., Ely, K.R., Shroot, B., and Fontana, J.A. Correlation of retinoid binding affinity to RAR with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells. Cancer Res. 55: 4446-4451. 1995.

      39. Zhang, X-k., Liu, Y., and Lee, M-O. Retinoid receptors in human lung cancer and breast cancer. Mutat. Res. 350: 267-277. 1996.

      40. Liu, Y., Lee, M-O., Wang, H-G., Li, Y., Hashimoto, Y., Klaus, M., Reed, J., and Zhang, X-k. RAR mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells. Mol. Cell. Biol. 16: 1138-1149. 1996.

      41. Sani, P., Zhang, X.-k., Hill, D.L., and Shealy, Y.F. Retinyl methyl ether: binding to transport proteins and effect on transcriptional regulation. Biochem. Biophys. Res. Comm. 223: 293-298. 1996.

      42. Sani, B.P., Venepally, P., Zhang, X-k., Hill, D.L., and Shealy, F. Biochemical characteristics and differentiating activity of 4-oxo analogs of retinoic acid. Anticancer Res. 16: 1177-1181. 1996.

      43. Wu, Q., Li, Y., Liu, R., Agadir, A., Lee, M-O., Liu, Y., and Zhang, X-k. Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization. EMBO J. 16: 1656-1669. 1997.

      44. Agadir, A., Shealy, Y. F., Hills, D.L., and Zhang, X-k. Retinyl methyl ether down-regulates activator protein 1 transcriptional activation in breast cancer cells. Cancer Res. 57: 3444-3450. 1997.

      45. Wu, Q., Dawson, M.I., Zheng, Y., Hobbs, P.D., Agadir, A., Jong, L., Li, Y., Liu, R., Lin, B., and Zhang, X-k. Inhibition of trans-RA-resistant human breast cancer cell growth by retinoid X-receptor-selective retinoids. Mol. Cell. Biol. 17: 6598-6608. 1997.

      46. Chao, W-r, Hobbs, P.D., Jong, L., Zhang, X-k., Zheng, Y., Wu, Q., Shroot, B., and Dawson, M.I. Effects of receptor class- and subtype-selective retinoids and an apoptosis-inducing retinoid on the adherent growth of the NIH:OVCAR-3 ovarian cancer cell line in culture. Cancer Lett. 115: 1-7. 1997.

      47. Giannini, G., Dawson, M.I., Zhang, X-k., and Thiele, C.J. Activation of three distinct RXR/RAR heterodimers induces growth arrest and differentiation of neuroblastoma cells. J. Biol. Chem. 272: 26693-26701. 1997.

      48. Li, Y., Dawson, M.I., Agadir, A., Lee, M-O., Jong, L., Hobbs, P.D., and Zhang, X-k. Regulation of RAR beta expression by RAR- and RXR-selective retinoids in human lung cancer cell lines: effect on growth inhibition and apoptosis induction. Int. J. Cancer 75: 88-95. 1998.

      49. Muccio, D.D., Brouillette, W.J., Breitman, T.R., Taimi, M., Emanuel, P.D., Zhang, X-k., Chen, G-q., Sani, B.P., Venepally, P., Lakshimi, R., Alam, M., Simpson-Herren, L., and Hill, D.L. Conformationally defined retinoic acid analogues. 4, potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias. J. Med. Chem. 41: 1679-1687. 1998.

      50. Liu, R., Takayama, S., Zheng, Y., Froesch, B., Chen, G-q., Zhang, X., Reed, J.C., and Zhang, X-k. Interaction of BAG-1 with retinoic acid receptor and its inhibition of retinoic acid-induced apoptosis in cancer cells. J. Biol. Chem. 273: 16985-16992. 1998.

      51. Li, Y., Lin, B., Agadir, A., Liu, R., Dawson, M.I., Reed, J.C., Fontana, J.A., Bost, F., Hobbs, P.D., Zheng, Y., Chen, G.Q., Shroot, B., Mercola, D., and Zhang, X-k. Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines. Mol. Cell. Biol. 18: 4719-4731. 1998.

      52. Dawson, M.I., Chao, W.R., Hobbs, P.D., and Zhang, X-k. Effects of trans-retinoic acid, 9-cis-retinoic acid, 1alpha, 25-(dihydroxy) vitamin D3 and a novel apoptosis-inducing retinoid on breast cancer and endothelial cell growth. Cancer Lett. 133: 1-8. 1998.

      53. Agadir, A., Lazzaro, G., Zheng, Y., Zhang, X-k., and Mehta, R.G. Resistance of HBL100 human breast epithelial cells to vitamin D action. Carcinogenesis 20: 577-582. 1999.

      54. Li, Y., Hashimoto, Y., Agadir, A., Kagechika, H., and Zhang, X-k. Identification of a novel class of retinoic acid receptor -selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells. J. Biol. Chem. 274: 15360-15366. 1999.

      55. Agadir, A., Chen, G-q., Bost, F., Li, Y., Mercola, D., and Zhang, X-k. Differential effect of retinoic acid on growth regulation by phorbol ester in human cancer cell lines. J. Biol. Chem. 274: 29779-29785. 1999.

      56. Lin, B., Chen, G-q., Xiao, D., Kolluri, S.K., Cao, X., Su, H., and Zhang, X-k. Orphan receptor COUP-TF is required for induction of retinoic acid receptor , growth inhibition and apoptosis by retinoic acid in cancer cells. Mol. Cell. Biol. 20: 957-970. 2000.

      57. Dawson, M.I., Hobbs, P.D., Jong, L., Xiao, D., Chao, W-r., Pan, C., and Zhang, X-k. sp2-bridged diaryl retinoids: effect of bridge-region substitution on retinoid X receptor (RXR) selectivity. Bioorg. Med. Chem. Lett. 10: 1307-1310. 2000.

      58. Dawson, M.I., Jong, L., Hobbs, P.D., Xiao, D., Feng, K.C., Chao, W-r., Pan, C., Fontana, J.A., and Zhang, X-k. 4-[3-(5,6,7,8-Tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl)-phenyl]benzoic acid and hetercyclic-bridged analogs are novel retinoic acid receptor subtype and retinoid X receptor alpha agonists. Bioorg. Med. Chem Lett. 10: 1311-1313. 2000.

      59. Lin, F., Xiao, D., Kolluri, S.K., and Zhang, X-k. Unique anti-activator protein-1 activity of retinoic acid receptor-. Cancer Res. 60: 3271-3280. 2000.

      60. Dawson, M.I., Zhang, X-k., Hobbs, P.D., and Jong, L. Synthetic retinoids and their usefulness in biology and medicine. Vitamin A and retinoids: an update of biological aspects and clinical applications. M.A. Livrea (ed.), Birkhäuser Verlag Basel/Switzerland. pp161-196. 2000.

      61. Li, H., Kolluri, S., Gu, J., Dawson, M.I., Cao, X., Hobbs, P., Lin, B., Chen, G-q., Lu, J-s., Lin, F., Xie, Z., Fontana, J. A., Reed, J. C., and Zhang, X-k. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 289: 1159-1164. 2000.

      62. Dawson, M.I., Park, J., Chen, G-q., Chao, W-r., Dousman, L., Waleh, N., Hobbs, P., Jong, L., Toll, L., Zhang, X-k., Gu, J., Agadir, A., Merchant, J., Bai, L., Verma, A., Thacher, S., Chandraratna, R., Shroot, B., and Hill, D. Retinoic acid (RA) receptor transcriptional activation correlates with inhibition of 12-O-Tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity by retonoids. A potential role for Trans-RA-induced ZBP-89 in ODC inhibition. Int. J. Cancer. 91: 8-21. 2001.

      63. Dawson, M.I., Hobbs, P., Peterson, V., Leid, M., Lange, C., Feng, K., Chen, G., Gu, J., Li, H., Kolluri, S., Zhang, X-k., Zhang, Y., and Fontana, J. Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. Cancer Research. 61: 4723-4730. 2001.

      64. Stelle-Perkins, G., Fang, W., Yang, X-H., Van Gele, M., Carling, T., Gu, J., Buyse, I.M., Fletcher, J.A., Liu, J., Bronson, R., Chadwick, R.B., de la Chapelle, A., Zhang, X-k., Speleman, F., and Huang, S. Tumor formation and inactivation of RIZ1, an R-binding member of a nuclear protein-methyltransferase superfamily. Genes Dev. 15: 2250-2262. 2001.

      65. Chen, G-q., Lin, B., Dawson, M.I., and Zhang, X-k. Nicotine modulates the effects of retinoids on growth inhibition and RAR expression in lung cancer cells. Int. J. Cancer. 99: 171-178. 2002.

      67. Zhang, Y., Dawson, M.I., Mohammad, R., Rishi, A.K., Farhana, L., Feng, K-C., Leid, M., Perterson, V., Zhang, X-k., Edelstein, M., Eilander, D., Biggar, S., Wall, N., Reichert, U., and Fontana, J.A. Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its non-retinoidal analog. Blood. 100: 2917-2925. 2002.

      68. Lin, F., Kolluri, S., Chen, G-q., and Zhang, X-k. Regulation of Retinoic Acid-induced Inhibition of AP-1 Activity by Orphan Receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor. J. Biol. Chem. 277: 21414-21422. 2002.

      69. Peterson, V.J., Barofsky, E., Deinzer, M.L., Dawson, M.I., Feng, K.C., Zhang, X-k., Madduru, M.R., and Leid, M. Mass-spectrometric analysis of agonist-induced retinoic acid receptor gamma conformational change. Biochemical Jour. 362: 173-181. 2002.

      70. Zhang, X-k. Vitamin A and apoptosis in prostate cancer. Endocrine-Related Cancer. 9: 87-102. 2002.

      71. Li, M., Song, S., Lippman, S.M., Zhang, X-k., Liu, X., Lotan, R., and Xu, X-c. Induction of Retinoic Acid Receptor- and Sensitivity to Retinoic Acid of Esophageal Cancer Cells Dependent on Cyclooxygenase-2 Expression. Oncogene. 21: 411-418. 2002.

      72. Dawson M.I. and Zhang, X-k. Discovery and design of retinoic acid receptor and retinoid X receptor class- and subtype-selective synthetic analogs of all-trans-retinoic acid and 9-cis-retinoic acid. Curr. Med. Chem. 9: 623-637. 2002.

      73. Zhang, Y., Dawson, M.I., Ning, Y., Polin, L., Parchment, R.E., Corbett, T., Mohammad, A.N., Feng, K-C., Farhana, L., Rishi, A.K., Hogge, D., Leid, M., Peterson, V.J., Zhang, X-k., Mohammad, R., Lu, J-S., Willman, C., VanBuren, E., Biggar, S., Edelstein, M., Eilender, D., and Fontana, J.A. Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog. Blood. 102: 3743-3752. 2003.

      74. Kolluri, S., Bruey-Sedano, N., Cao, X., Lin, B., Lin, F., Han, Y-h., Dawson, M.I., and Zhang, X-k. Mitogenic Effect of Orphan Receptor TR3 and its Regulation by MEKK1 in Lung Cancer Cells. Mol. Cell. Biol. 23: 8651-8667. 2003.

      75. James, S., Lin, F., Kolluri, S., Dawson, M.I., and Zhang, X-k. Regulation of retinoic acid receptor  expression by peroxisome proliferator-activated receptor  ligands in cancer cells. Cancer Res. 63: 3531-3538. 2003.

      76. Liu, Y., Ren, H., Wu, C., Bai, S., Zhang, X-k., and Ru., B. Lin, B. Attenuation of zinc-induced neuronal death by the interaction of growth inhibitory factor with Rab3A in rat hippocampal neurons. Neurosci Lett. 358: 149-152, 2004.

      77. Lin, B., Kolluri, S., Lin, F., Liu, W., Han, Y-h., Cao, X., Dawson, M.I., Reed, J.C., and Zhang, X-k. Conversion of Bcl-2 from Protector to Killer by Interaction with Nuclear Orphan Receptor Nur77/TR3. Cell. 116: 527-540. 2004.

      78. Castro-Obregón, S., Rao, R., del Rio, G., Chen, S., Poksay, K., Rabizadeh, S., Vesce, S., Zhang, X-k., Swanson, R., and Bredesen, D. Alternative, non-apoptotic programmed cell death: mediation by Arrestin 2, ERK2 and Nur77. J Biol Chem. 279: 17543-17553. 2004.

      79. Dawson, M.I., Harris, D., Liu, G., Hobbs, P., Lange, C., Jong, L., Bruey-Sedano, N., James, S., Zhang, X-k., Peterson, V., Leid, M., Farhana, L., Rishi, A., and Fontana, J. Antagonist Analogue of 6-[3’-(1-Adamantyl)-4’–hydroxyphenyl]-2-naphthalenecarboxylic Acid (AHPN) Family of Apoptosis Inducers That Effectively Blocks AHPN-Induced Apoptosis but Not Cell-Cycle Arrest. J. Med. Chem. 47: 3518-3536. 2004.

      80. Cavasotto, C.N., Liu, G., James, S.Y., Hobbs, P.D., Peterson, V.J., Bhattacharya, A.A., Kolluri, S.K., Zhang, X-k., Leid, M., Abagyan, R., Liddington, R.C., and Dawson,.M.I. Determinants of Retinoid X Receptor Transcriptional Antagonism. J. Med. Chem. 47: 4360-4372. 2004.

      81. Carling, T., Kim, K.C., Yang, X.H., Gu, J., Zhang, X-k., and Huang, S. A histone methyltransferase is required for maximal response to female sex hormones. Mol. Cell Biol. 24: 7032-7042. 2004.

      82. Cao, X., Liu, W., Lin, F., Li, H., Kolluri, S.K., Lin, B., Han, Y-h, Dawson, M.I., and Zhang, X-k. Retinoid X receptor regulates Nur77/TR3-dependent apoptosis by modulating its nuclear export and mitochondrial targeting. Mol. Cell Biol. 24: 9705-9725. 2004.

      83. Lee, K-W., Ma, L., Yan, X., Liu, B., Zhang, X-k., and Cohen, P. Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXR/Nur77. J. Bio. Chem. 280: 16942-16948. 2005.

      84. Kolluri, S.K., Corr, M., James, S.Y., Bernasconi, M., Lu, D., Liu, W., Cottam, H.B., Leoni, L.M., Carson, D.A., and Zhang, X-k. The R-enantiomer of the Non-steroidal Anti-inflammatory Drug Etodolac Binds Retinoid X Receptor and Induces Tumor-selective Apoptosis. PNAS. 102: 2525-2530. 2005.

      85. Han, Y.H., Cao, X., Lin, B., Lin, F., Kolluri, S.K., Reed, J.C., Dawson, M.I., and Zhang, X-k. Regulation of nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene. 25:2974-2986. 2005.

      86. Moll, U.M., Marchenko, N., and Zhang, X-k. P53 and Nur77/TR3-Transcription Factors that Target Mitochondria for Cell Death Induction. Oncogene 25: 4725-4743. 2006.

      87. Stebbins, J., Jung, D., Leone, M, Zhang, X-k., and Pellecchia, M. A Structure Based Approach to RXR Inhibition. JBC 281: 16643-16648. 2006.

      88. Zeng, J., Sun, D-F., Wang, L., Cao, X., Qi, J-b., Yang, T., Hu, C-q., Liu, W., and Zhang, X-k. Hypericum sampsonii Induces Apoptosis and Nuclear Export of Retinoid X Receptor-alpha. Carcinogenesis. 27: 1991-2000. 2006.

      89. Wang, J.G., Barsky, L.W., Davicioni, E., Weinberg, K.I., Triche, T.J., Zhang, X-k., and Wu, L. Retinoic acid induces leukemia cell G1 arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RARalpha. FASEB J. 20: 2142-2144. 2006.

      90. Zhai, DY., Sergienko, E., Kitada, S., Luciano, F., Satterswait, AC., Zhang, XK., and Reed, JC. Exploiting the TR3 interaction with Bcl-2 as a novel therapeutic strategy of cancer and leukemia therapy. BLOOD. 108: 80A-80A 256 Part 1 Nov. 16, 2006.

      91. Andreeff, M., Konopleva, M.,Watt, JC., Samudio, IJ., Satterthwait, AC., Kitada, S., Zhang, XK., and Reed, JC. A novel peptide containing a nine amino acid sequence from Nur77 induces Bcl-2-dependent apoptosis in AML. BLOOD. 108: 736A-736A 2607 Part 1 Nov. 16, 2006.

      92. Hexin Chen, Huiping Zhang, Jishin Lee, Xiaohui Liang, Xinyan Wu, Tao Zhu,Pang-kuo Lo, Xiaokun Zhang and Saraswati Sukumar. HOXA5 Acts Directly Downstream of Retinoic Acid Receptor and Contributes to Retinoic Acid–Induced Apoptosis and Growth Inhibition. Cancer Res. 67: 8007-8013. 2007.

      93. Zhang, X.-k. Targeting Nur77 Translocation. Expert Opinion on Therapeutic Targets. 11: 59-79. 2007.

      94. Dawson, MI., Xia, ZB., Liu, G., Fontana, JA., Farhana, L., Patel, BB., Arumugarajah, S., Bhuiyan, M., Zhang, XK., Han, YH., Stallcup, WB., Fukushi, JI., Mustelin, T., Tautz, L., Su, Y., Harris, DL., Waleh, N., Hobbs, PD., Jong, L., Chao, WR., Schiff, LJ., Sani, BP. An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: Effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity. J. Med. Chem. 50: 2622-2639. 2007.

      95. Bisson, WH., Cheltsov, AV., Bruey-Sedano, N., Lin, B., Chen, J., Goldberger, N., May, LT., Christopoulos, A., Dalton, JT., Sexton, PM., Zhang, XK., and Abagyan, R. Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc. Nat. Acad. Sci.. 104: 11927-11932. 2007.

      96. Luciano, F., Krajewska, M., Ortiz-Rubio, P., Krajewski, S., Zhai, D., Faustin, B., Bruey, J.M,. Bailly-Maitre, B., Lichtenstein, A., Kumar Kolluri, S., Satterthwait ,A.C., Zhang, X-k., Reed, J.C. Nur77 converts phenotype of Bcl-B, an anti-apoptotic protein expressed in plasma cellsand myeloma. BLOOD, 109: 3849-3855. 2007.

      97. Zeng, J-z., and Zhang, X-k. Nongenomic Actions of Retinoids: Role of Nur77 and RXR in the Regulation of Apoptosis and Inflammation. Anti-Inflammatory & Anti-Allergy Agents Medicinal Chem., 6: 315-331. 2007.

      98. Dawson MI, Xia Z, Jiang T, Ye M, Fontana JA, Farhana L, Xue LP, Patel B, Bhuiyan M, Pellicciari R, Macchiarulo A, Nuti R, Zhang X-K, Han Y-H, Tautz L, Waleh N, Hobbs P D, Jong L, Chao W, Feng G-S, and Su Y. Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: Effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SHP-2 protein-tyrosine phosphatase activity. J. Med. Chem. 51: 5650-5652, 2008.

      99. Chai, D., Wang, B., Shen, L., Pn, J., Zhang, X-k., and He, B. RXR agonists inhibits high glucose induced oxidative stress by repressing PKC activity in human endothelial cells. Free Radical Biology & Medicine, 44: 1334-1347. 2008.

      100. Liu, J., Zhou, W., Li, S.S., Sun, Z., Lin, B., Lang, Y.Y., He, J-Y., Cao, X., Yan, T., Wang, L., Lu, J., Han, Y-h., Cao, Y., Zhang, X.-k., and Zeng J-z. Modulation of Orphan Nuclear Receptor Nur77-Mediated Apoptotic Pathway by Acetylshikonin and Analogues. Cancer Res., 68: 8871-8880. 2008.

      101. Kolluri, S., Zhu, X., Zhou, X., Lin, B., Chen, Y., Sun, K., Tian, X., Town, J., Cao, X., Lin, F., Zhai, D., Kitada, S., Luciano, F., O’Donnell, E., Cao, Y., He, F., Lin, J., Reed, J.C., Satterthwait, A.C., and Zhang, X-k. A Short Nur77-Derived Peptide Converts Bcl-2 from a Protector to a Killer. Cancer Cell. 14: 285-298. 2008.

      102. Han, Y.H., Zhou, H., Kim, J.H., Yan, T.D., Lee, K.H., Wu, H., Lin, F., Lu, N., Liu, J.,Zeng, J.Z., and Zhang, X.k. A unique cytoplasmic localization of RARgamma and its regulations. J. Biol. Chem. 284:18503-18514. 2009.

      103. Dawson, M.I., Ye, M., Cao, X., Farhana, L., Hu, Q.Y., Zhao, Y., Xu, L.P., Kiselyuk, A., Correa, R.G., Yang, L., Hou, T., Reed, J.C., Itkin-Ansari, P., Levine, F., Sanner, M.F., Fontana, J.A., Zhang, X.K. Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl) methyl-4-trifluoromethylbenzene. ChemMedChem. 4:1106-19. 2009.

      104. Lu J, Dawson MI, Hu QY, Xia Z, Dambacher JD, Ye M, Zhang X-K, and Li E. The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand-binding domain. Mag. Reson. Chem. 47:1071-1080, 2009.

      105. You, X., Zhang, Y.W., Chen, Y., Huang, X, Xu, R., Cao, X.H., Chen, J., Zhang, X.K., and Xu, H.X. Retinoid X receptor- mediates (R)-flurbiprofen’s effect on the levels of Alzheimer’s -amyloid4. Journal of Neurochemistry, 111: 142-149. 2009.

      106. Yan, T.D., Wu, H., Zhang, H.P., Lu, N., Ye, P., Yu, F.H., , Zhou, H., Li, W.G., Cao, X., Lin, Y.Y., He, J.Y., Gao, W.W., Zho, Y., Xie, L., Chen, J.B., Zhang, X.K., and Zeng, J.Z. Oncogenic potential of retinoic acid receptor-gamma in hepatocellular carcinoma. Cancer Res. 70: 2285-2295. 2010.

      107. Zhou, H., Liu, W., Su, Y., Wei, Z., Liu, J., Kolluri, S.K., Wu, H., Cao, Y., Chen, J., Wu, Y., Yan, T., Cao, X., Gao, W., Molotkov, A., Jiang, F., Li, W-G., Lin, B., Zhang, H-P., Yu, J., Luo, S-P., Zeng, J-Z., Duester, G., Huang, P-Q., and Zhang, X-k. NSAID Sulindac and Its Analogs Bind RXR and Inhibit RXR-dependent AKT Signaling. Cancer Cell. 17: 560-573. 2010.

      108. Kim, B.Y., Yang, J.S., Kwak, S.Y., Zhang, X.K., Han, Y.H. NEMO stabilizes c-Myc through direct interaction in the nucleus. FEBS Lett. 584: 4524-4530. 2010.

      109. Wu, H., Lin, Y., Li, W., Sun, Z., Gao, W., Zhang, H., Xie, L., Jiang, F., Qin, B., Yan, T., Chen, L., Zhao, Y., Cao, X., Wu, Y., Lin, B., Zhou, H., Wong, A., Zhang, X-k., and Zeng, J-Z. Regulation of Nur77 expression by -catenin and its mitogenic effect in colon cancer cells. FASEB J. 25: 192-205. 2011

      110. Cheng, Z. Völkers, M., Din, S, Avitabile, D. Khan, M., Gude, N., Mohsin, S., Bo, T., Truffa, S., Alvarez, R., Mason, M., Fischer, K.M., Konstandin, M.H., Zhang, X.K., Brown, J.H., and Sussman, M.A. Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis. Eur Heart J. Eur 32(17):2179-88, 2011.

      111. Dawson, M.I., Lu, J., Li, E., Xia, Z., Ye, M., Zhang, X.K., Hu, Q-Y. Retinoids, Burger’s Medicinal Chemistry, Drug Discovery and Development, Book Chapter, In Press, Corrected Proof. 2010.

      112. Duan YH, Dai Y, Wang GH, Chen HF, Gao H, Chen JB, Yao XS, Zhang XK. Xanthone and benzophenone glycosides from the stems of Cratoxylum formosum ssp. pruniflorum. Chem Pharm Bull (Tokyo), 59(2):231-4, 2011.

      113. Liu, DP, Luo Q, Wang GH, Xu Y, Zhang XK, Chen QC, Chen HF. Furocoumarin derivatives from radix Angelicae dahuricae and their effects on RXRα transcriptional regulation. Molecules 16(8):6339-48, 2011.

      114. Lin T, Wang GH, Lin X, Hu ZY, Chen QC, Xu Y, Zhang XK, Chen HF. Three new oblongolides from Phomopsis sp. XZ-01, an endophytic fungus from Camptotheca acuminate. Molecules 16(4):3351-9, 2011.

      115. Sun, Z, Cao, X, Jiang, M-M, Qiu, Y, Zhou, H, Chen, L, Qin, B, Wu, H, Jiang, F, Chen, J, Liu, J, Dai, Y, Chen, HF, Hu, QY, Wu, Z, Zeng, J-z, Yao, XS, and Zhang, XK. Inhibition of -catenin Signaling by Nongenomic Action of Orphan Nuclear Receptor Nur77. Oncogene In press, 2011.

      116. Zhang, X-k., Hoffmann, B., Tran, P., Graupner, G., and Pfahl, M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature (London) 355: 441-446. 1992.

      117. Zhang, X-k., Lehmann, J.M., Hoffmann, B., Dawson, M., Cameron, J., Graupner, G., Hermann, T., Tran, P., and Pfahl, M. Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature (London) 358: 587-591. 1992.

      118. Liu, Y., Lee, M-O., Wang, H-G., Li, Y., Hashimoto, Y., Klaus, M., Reed, J., and Zhang, X-k. RAR mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells. Mol. Cell. Biol. 16: 1138-1149. 1996.

      119. Wu, Q., Li, Y., Liu, R., Agadir, A., Lee, M-O., Liu, Y., and Zhang, X-k. Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors Nur77 and COUP-TF and their heterodimerization. EMBO J. 16: 1656-1669. 1997.

      120. Li, Y., Lin, B., Agadir, A., Liu, R., Dawson, M.I., Reed, J.C., Fontana, J.A., Bost, F., Hobbs, P.D., Zheng, Y., Chen, G.Q., Shroot, B., Mercola, D., and Zhang, X-k. Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines. Mol. Cell. Biol. 18: 4719-4731. 1998.

      121. Li, H., Kolluri, S., Gu, J., Dawson, M.I., Cao, X., Hobbs, P., Lin, B., Chen, G-q., Lu, J-s., Lin, F., Xie, Z., Fontana, J. A., Reed, J. C., and Zhang, X-k. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 289: 1159-1164. 2000.

      122. Lin, B., Kolluri, S., Lin, F., Liu, W., Han, Y-h., Cao, X., Dawson, M.I., Reed, J.C., and Zhang, X-k. Conversion of Bcl-2 from Protector to Killer by Interaction with Nuclear Orphan Receptor Nur77/TR3. Cell. 116: 527-540. 2004.

      123. Kolluri, S.K., Corr, M., James, S.Y., Bernasconi, M., Lu, D., Liu, W., Cottam, H.B., Leoni, L.M., Carson, D.A., and Zhang, X-k. The R-enantiomer of the Non-steroidal Anti-inflammatory Drug Etodolac Binds Retinoid X Receptor and Induces Tumor-selective Apoptosis. Proc. Natl. Acad. Sci. 102: 2525-2530. 2005.

      124. Kolluri, S., Zhu, X., Zhou, X., Lin, B., Chen, Y., Sun, K., Tian, X., Town, J., Cao, X., Lin, F., Zhai, D., Kitada, S., Luciano, F., O’Donnell, E., Cao, Y., He, F., Lin, J., Reed, J.C., Satterthwait, A.C., and Zhang, X-k. A Short Nur77-Derived Peptide Converts Bcl-2 from a Protector to a Killer. Cancer Cell. 14: 285-298. 2008.

      125. Zhou, H., Liu, W., Su, Y., Wei, Z., Liu, J., Kolluri, S.K., Wu, H., Cao, Y., Chen, J., Wu, Y., Yan, T., Cao, X., Gao, W., Molotkov, A., Jiang, F., Li, W-G., Lin, B., Zhang, H-P., Yu, J., Luo, S-P., Zeng, J-Z., Duester, G., Huang, P-Q., and Zhang, X-k. NSAID Sulindac and Its Analogs Bind RXR and Inhibit RXR-dependent AKT Signaling. Cancer Cell. 17: 560-573. 2010.

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      6 全反式視黃酸對癌細(xì)胞凋亡的誘導(dǎo) 吳喬; 鄭耘; 張曉坤 廈門大學(xué)腫瘤細(xì)胞工程國家專業(yè)實(shí)驗(yàn)室; 加州La Jolla癌癥研究中心 【期刊】癌癥 1998-06-05

      7 視黃素誘導(dǎo)的癌細(xì)胞凋亡及其對癌細(xì)胞生長抑制的相關(guān)性 吳喬; 鄭耘; 張曉坤 廈門大學(xué)腫瘤細(xì)胞工程國家專業(yè)實(shí)驗(yàn)室暨國家教委開放研究實(shí)驗(yàn)室 【期刊】廈門大學(xué)學(xué)報(bào)(自然科學(xué)版) 1998-03-05

      8 COUP-TE和RAR β受體的表達(dá)影響癌細(xì)胞對視黃酸的敏感性 吳喬; 張曉坤 廈門大學(xué)腫瘤細(xì)胞工程國家專業(yè)實(shí)驗(yàn)室; La Jolla癌癥研究中心; Burnham研究所; 美國加州 【期刊】細(xì)胞生物學(xué)雜志 1998-02-15

      9 大黃素誘導(dǎo)癌細(xì)胞凋亡和抑制視黃醇X受體的轉(zhuǎn)錄激活功能 和付林; 王力; 張曉坤; 曾錦章 中國科學(xué)院上海生命科學(xué)研究院; 中國科學(xué)院上海生命科學(xué)研究院 上海; 廈門大學(xué)生物醫(yī)學(xué)研究院; 福建廈門; 廈門大學(xué)生物醫(yī)學(xué)研究院 【期刊】藥學(xué)學(xué)報(bào) 2008-04-12

      10 孤生受體的相互作用對視黃酸應(yīng)答元件的影響 吳喬; 張曉坤 廈門大學(xué)腫瘤細(xì)胞工程國家專業(yè)實(shí)驗(yàn)室 【期刊】中國生物化學(xué)與分子生物學(xué)報(bào) 1999-02-10

      榮譽(yù)獎(jiǎng)勵(lì):


      1. 1984年至1986獲中國政府獎(jiǎng)學(xué)金。

      2. 1988年獲美國 Cathy(凱茜)綜合醫(yī)院獎(jiǎng)(Cathy General Hospital Award)。

      3. 1990年至1992年獲博士后獎(jiǎng)學(xué)金。

      4. 2001年獲“杰出原創(chuàng)獎(jiǎng)”(Wonderful Original Work)。

      5. 2008年入選第一批“千人計(jì)劃”。

      資料更新中……

      媒體報(bào)道一:


      2008風(fēng)云人物癌細(xì)胞凋亡成果撼動(dòng)世界 專訪張曉坤教授

      編者按:2月4日是國際癌癥日,世界衛(wèi)生組織官員在2008年國際腫瘤學(xué)年會上提出警告,到2010年,癌癥將取代心血管病成為世界頭號殺手。全世界的科學(xué)家都在關(guān)注癌癥研究,聯(lián)手狙擊這個(gè)頭號殺手。2008年,張曉坤教授在著名期刊《Cancer cell》發(fā)表抗癌新見解,他發(fā)現(xiàn)的一個(gè)抗癌神奇小肽為癌癥治療開辟了一條嶄新的道路,我們離終結(jié)癌癥的那天有多遠(yuǎn)?生物通獨(dú)家專訪2008年生命科學(xué)十大風(fēng)云人物抗癌先鋒:張曉坤。

      生物通:您長期研究癌癥,能概括性地介紹一下您的研究經(jīng)歷和階段性成果嗎?

      張曉坤:二十多年來我一直在研究核受體調(diào)控癌細(xì)胞生長與死亡的分子作用機(jī)制,以鑒定新的藥物作用靶點(diǎn)和開發(fā)新型的抗癌藥物。我認(rèn)為我們對癌細(xì)胞的了解還非常不夠,這阻礙了我們在癌癥治療上面的發(fā)展,F(xiàn)在國內(nèi)外對開發(fā)靶點(diǎn)藥物非常熱門。但哪個(gè)蛋白可作為靶點(diǎn)呢?又如何對這個(gè)靶點(diǎn)進(jìn)行開發(fā)呢?這不但是我們國內(nèi)也是國際上所面臨的重要問題。我非常有幸在美國與我的合作者發(fā)明了一個(gè)抗癌藥物,叫Targretin®或Bexarotene。這個(gè)藥在99年被美國FDA批準(zhǔn)用于治療皮膚T淋巴細(xì)胞癌,前年轉(zhuǎn)讓給日本的一家叫Eisai的公司。Targretin®是國際上第一個(gè)針對核受體RXR為靶點(diǎn)的抗癌藥物。它的發(fā)明應(yīng)該說是靶點(diǎn)藥物開發(fā)的一個(gè)成功例子,是建立在大量的基礎(chǔ)理論研究上的,包括我早期發(fā)表在《自然》刊物上的兩篇闡述核受體RXR信號轉(zhuǎn)導(dǎo)通路的文章(Nature 355: 441-446, 1992; Nature 358: 587-591, 1992)。沒有對RXR分子作用機(jī)制的認(rèn)識,就不可能有Targretin®/bexarotene抗癌新藥的發(fā)現(xiàn)。

      生物通:2008年您在Cancer Cell上發(fā)表文章,找到一種具有殺死癌細(xì)胞功效的神奇小肽,您能詳細(xì)介紹一下如何發(fā)現(xiàn)這個(gè)神奇小肽的嗎?.

      張曉坤:這個(gè)小肽的發(fā)現(xiàn)不是偶然的,是我們長年工作的一個(gè)結(jié)果,建立在我們多年的基礎(chǔ)理論研究上的。我的研究領(lǐng)域是核受體(Nuclear Receptor)。核受體這個(gè)超大家族包括類固醇激素受體、甲狀腺激素受體、性激素受體、維生素A/D受體及多種孤生受體。這個(gè)超家族成員是調(diào)控人體的生長發(fā)育、細(xì)胞分化,以及體內(nèi)許多生理、代謝過程的重要蛋白。我們現(xiàn)在用的很多藥物都是通過核受體起作用的。 我們早期對核受體的認(rèn)識是這類蛋白質(zhì)是在細(xì)胞核里作為轉(zhuǎn)錄因子直接參與調(diào)控基因的表達(dá)的。

      轉(zhuǎn)折點(diǎn)

      但在2000年我們在《科學(xué)》雜志上報(bào)道了核受體Nur77在細(xì)胞核外與線粒體相作用的一條獨(dú)特有效的誘導(dǎo)癌細(xì)胞凋亡的調(diào)控通路(Science 289: 1159-1164, 2000),開辟了核受體非基因型作用機(jī)制與功能的研究領(lǐng)域。這個(gè)發(fā)現(xiàn)對抗癌藥物的開發(fā)是非常有意義的,因?yàn)槲覀冎勒T導(dǎo)癌細(xì)胞凋亡是一條很有效抑癌途徑。經(jīng)過幾年的努力我們在2004年在《細(xì)胞》雜志上報(bào)道了核受體Nur77誘導(dǎo)癌細(xì)胞凋亡是通過與抗凋亡蛋白Bcl-2的相互作用來完成的(Cell 116: 527-540, 2004)。我們在這篇文章里很系統(tǒng)地闡述了Bcl-2的促凋亡功能,為將保護(hù)癌細(xì)胞死亡的Bcl-2蛋白轉(zhuǎn)變成癌細(xì)胞殺手提供了重要的分子作用基礎(chǔ)。

      08年新發(fā)現(xiàn)撼動(dòng)科學(xué)界

      我們現(xiàn)在發(fā)現(xiàn)的這個(gè)殺癌小肽就是建立在這些大量的基礎(chǔ)理論研究上的。神奇小肽NuBCP-9及對映體(鏡象分子)的多肽好似一個(gè)分子開關(guān)作用于Bcl-2,使Bcl-2從一個(gè)保護(hù)癌細(xì)胞免受程序性死亡(細(xì)胞凋亡)調(diào)控轉(zhuǎn)變?yōu)槟軌驓⑺腊┘?xì)胞的蛋白。這個(gè)發(fā)現(xiàn)應(yīng)該說是近年來在腫瘤生物學(xué)領(lǐng)域的一個(gè)比較重要的發(fā)現(xiàn),將為治療癌癥開辟一條“化敵為友”的新途徑,因此在國際生物醫(yī)學(xué)科學(xué)研究領(lǐng)域激起了很大的反響和廣泛的關(guān)注。近期,《自然》出版集團(tuán)(The Nature Publishing Group)出版的三份世界著名刊物《自然-化學(xué)生物學(xué)》(Nature Chemical Biology)、《自然-新藥開發(fā)綜述》(Nature Reviews Drug Discovery)和《SciBX》(Science-Business eXchange)都相繼介紹了我們這個(gè)研究成果,并邀請相關(guān)領(lǐng)域的專家對這個(gè)發(fā)現(xiàn)的理論意義及應(yīng)用前景進(jìn)行評論。一致認(rèn)為我們的研究加深了對細(xì)胞凋亡誘導(dǎo)的認(rèn)識,為抗癌藥物的開發(fā)提供了一個(gè)新的途徑,具有重大的意義,影響深遠(yuǎn)。

      生物通:實(shí)在是太奇妙了,您的研究開辟了一條新的研究道路,Bcl-2這個(gè)原本是保護(hù)癌細(xì)胞逃避細(xì)胞凋亡的蛋白經(jīng)過神奇小肽的處理竟然變?yōu)榭梢詺⑺腊┘?xì)胞的殺手。神奇小肽的應(yīng)用前景如何?

      張曉坤:就小肽而言,它可以直接殺死癌細(xì)胞。目前我們只是在實(shí)驗(yàn)室階段取得了成效,這個(gè)小肽在動(dòng)物身上可以很有效地殺死癌細(xì)胞,但我們并沒有進(jìn)行人的臨床試驗(yàn)。所以把它作為抗癌藥物用在人身上還為時(shí)太早。當(dāng)然如果一切順利的話,它可以象打針吃藥一樣地用在病人身上。

      生物通: 緊接著下來,您的研究計(jì)劃是什么?

      張曉坤:對于我們的下一步的實(shí)驗(yàn)計(jì)劃,我們會盡快證明這個(gè)小肽是不是有可能可以直接用在癌癥的治療上。這需要大量的動(dòng)物與臨床試驗(yàn)來證明它的活性與安全性。我們同時(shí)也準(zhǔn)備以這個(gè)小肽為基礎(chǔ)來尋找有類似作用的小分子化合物。小分子化合物有可能會比小肽更有開發(fā)價(jià)值。

      生物通:您的這項(xiàng)發(fā)現(xiàn)是否申請了專利

      張曉坤:我們的發(fā)現(xiàn)已在美國申請了專利。

      生物通:您能談一下癌癥研究的現(xiàn)狀嗎,最有前途的治療手段將是什么手段。

      張曉坤:現(xiàn)在癌癥研究的進(jìn)展還是令人鼓舞的。近年來有幾個(gè)很有效的靶點(diǎn)藥物已經(jīng)被廣泛地應(yīng)用到一些癌癥病人的治療。靶點(diǎn)藥物的開發(fā)在國際上是很熱門的。幾個(gè)很重要的癌癥藥物作用靶點(diǎn)與作用通路已經(jīng)被找到,對于這些作用靶點(diǎn)與通路,我們應(yīng)該要有更深刻的認(rèn)識,才能更有效地利用它們。干細(xì)胞及microRNA的研究很有可能會給癌癥研究帶來突破性的發(fā)現(xiàn)。近年來基因組學(xué)及蛋白組學(xué)的進(jìn)展也很快,為尋找癌細(xì)胞的生物學(xué)標(biāo)志提供了重要的技術(shù)手段。這些生物學(xué)標(biāo)志的發(fā)現(xiàn)與鑒定對以后的個(gè)性化治療是很重要的。

      文章來源:《生物通》2009年02月20日

      媒體報(bào)道二:


      廈門大學(xué)90周年校慶特別報(bào)道:張曉坤他讓癌細(xì)胞“改惡從善”

      核心提示撇開深?yuàn)W的術(shù)語,廈門大學(xué)生物醫(yī)學(xué)院院長張曉坤從事的是和人類健康有關(guān)的生物醫(yī)藥研究,他的最大成就是:千方百計(jì)通過合成化合物來“策劃”人體內(nèi)的癌細(xì)胞“叛變”,將其化敵為友,從而四兩撥千斤地尋找治療癌癥的藥物。

      廈大校園是全國最美的

      問:廈大校園哪處最美?

      張曉坤:現(xiàn)在我認(rèn)為是芙蓉湖,以前我認(rèn)為是建南大會堂那片,特別是密密麻麻的棕櫚樹,在那邊散步真好。

      問:廈大的魅力在哪里?

      張曉坤:作為一個(gè)廈大人感到驕傲的地方是它的校園,到每個(gè)地方,我們就會講,廈大是全國最美的。另一方面是廈大的嘉庚精神、應(yīng)該說,這幾年,廈大做得不錯(cuò),但是,我認(rèn)為還需要更多的進(jìn)步,因?yàn)槲覀冊诎l(fā)展,別人也在發(fā)展,我們要趕上去,就要花比別人更多的力量。

      五人抱團(tuán)回國服務(wù)廈大

      祖籍惠安的廈大生物醫(yī)學(xué)院院長張曉坤在1978年考上廈大時(shí),只有15歲。從生物系畢業(yè)后,曾留校任教,之后赴美留學(xué)。獲得博士學(xué)位后,一直在美國加利福尼亞州的伯恩翰姆(Burnham)研究所的癌癥研究中心工作。

      很顯然,張曉坤之所以回到廈大,家鄉(xiāng)和母校的情結(jié)發(fā)揮了很大作用。但是,張曉坤說,真正促動(dòng)他回國的是在2006年,廈大花大力氣發(fā)展和人類健康有關(guān)的生物醫(yī)藥研究的創(chuàng)新舉措。

      當(dāng)時(shí),廈大做出了一個(gè)不同尋常的決定,成立生物醫(yī)學(xué)研究院,交給在海外的五人“空降”小組管理,為首的就是張曉坤。

      張曉坤說,“五人小組”的成員,都是長期在海外工作并已取得突出成就的中國留學(xué)生,其中,有四人畢業(yè)于廈大,張曉坤等三人同在有生物硅谷之稱的伯恩翰姆研究所工作。

      2009年,中國推出引進(jìn)海外高級人才的“千人計(jì)劃”,五人小組中,包括張曉坤在內(nèi)的三人入選。張曉坤說,這足見“五人小組”的分量。

      “五人小組”將廈大生物醫(yī)學(xué)研究院研究的方向直接設(shè)定在癌癥、老年癡呆癥、糖尿病、SARS等人們最關(guān)心的幾大疾病。更重要的是,張曉坤說,我們要把我們的研究成果轉(zhuǎn)化為“現(xiàn)實(shí)的東西”,即開發(fā)出能治療幾大重大疾病的藥物。

      開發(fā)的抗癌藥得到國際認(rèn)可

      從學(xué)術(shù)角度來說,張曉坤是尋找通過核受體起作用的癌癥藥物的科學(xué)家。

      核受體是人體的一種蛋白質(zhì),它控制人體中激素、維生素、營養(yǎng)素等是否發(fā)揮作用,例如,你是男生,那么,就必須通過核受體來傳達(dá)雄性激素的一些功能。換句話說,核受體在人類健康中發(fā)揮著相當(dāng)大的作用——一旦激素失調(diào),人就會出現(xiàn)問題。

      核受體因此也被證明是藥物開發(fā)的第二大“開關(guān)”,世界上有13%的藥物是通過核受體來發(fā)揮作用,例如,乳腺癌和激素有關(guān),激素的核受體就被科學(xué)家們開發(fā)來治療乳腺癌。

      不太為國人所知的是,在美國,張曉坤和他的合作者已經(jīng)開發(fā)出世界上第一個(gè)針對一個(gè)名為“RXR”核受體的治癌藥物蓓薩羅丁(Targretin),主治皮膚癌。它已在1999年被美國食品藥物管理局(FDA)批準(zhǔn)生產(chǎn),在臨床上廣泛應(yīng)用。

      張曉坤說,這類核受體藥物就是俗稱的“靶點(diǎn)藥”,即我們把導(dǎo)致皮膚癌的關(guān)鍵蛋白(俗稱“靶點(diǎn)”)找到,然后,我們制造小分子“導(dǎo)彈”射向這個(gè)蛋白。

      張曉坤說,由于“靶向”十分明確,治療效果好,“靶向藥”是現(xiàn)在醫(yī)藥發(fā)展的一個(gè)方向。

      神奇小肽能把癌蛋白“化敵為友”

      使張曉坤被國內(nèi)業(yè)界所知的是,2008年,他和他的團(tuán)隊(duì)在廈大宣布合成一種被稱為“神奇小肽”的化合物,它可以使人體中一種蛋白質(zhì)從癌細(xì)胞“保護(hù)者”,“叛變”為能夠殺死癌細(xì)胞的“殺手”,換句話說,它能把癌蛋白“化敵為友”。

      張曉坤說,“神奇小肽”能直接作用于一種人體內(nèi)名為“Bcl-2”的蛋白質(zhì)——每個(gè)人都有“Bcl-2”這種蛋白質(zhì),而且,“Bcl-2”的家族成員眾多,有些控制細(xì)胞的“生”,有些則控制細(xì)胞的“死”,它們之間相互控制,取得平衡。在患上癌癥后,人體會在腫瘤中大量制造“Bcl-2”,從而使癌細(xì)胞不死,但是,“Bcl-2”本身的遺傳信息上同樣具備能殺死細(xì)胞的功能,這種“生”與“死”之間角色的轉(zhuǎn)換,就像開關(guān)一樣控制著癌細(xì)胞。

      通俗地說,張曉坤等人發(fā)現(xiàn)的這種神奇的小肽,就像一把能夠開啟“Bcl-2”這個(gè)控制癌細(xì)胞開關(guān)的“鑰匙”,使之能啟動(dòng)殺死癌細(xì)胞的程序。

      更為關(guān)鍵的是,這種肽十分容易合成,換句話說,這一新發(fā)現(xiàn)使科學(xué)家能夠基于Bcl-2蛋白構(gòu)象變化尋找新型治療藥物,為抗癌藥物的研發(fā)提供了一個(gè)新方向。2008年12月,《自然》(Nature)旗下3個(gè)子刊發(fā)表文章對這個(gè)神奇的小肽進(jìn)行了高度的肯定。

      新發(fā)現(xiàn)與可服用的藥物距離更近

      不過,和“神奇小肽”相比,2010年張曉坤和他的課題組在廈大發(fā)現(xiàn)的一種名為“K-80003”的抗癌藥物分子,可能和可服用的藥物距離更近。

      張曉坤說,這種“K-80003”被證明作用于癌細(xì)胞中特有的靶分子“tRXRα”蛋白時(shí),不但能夠抑制癌細(xì)胞生長,而且還能激活體內(nèi)其他細(xì)胞因子殺滅癌細(xì)胞!皌RXRα”蛋白是細(xì)胞在癌變過程中所產(chǎn)生的。

      這類蛋白之所以“叛變”為癌蛋白,涉及張曉坤課題組的另一個(gè)關(guān)鍵發(fā)現(xiàn),張曉坤說,我們發(fā)現(xiàn)它在核受體里面時(shí),它就發(fā)揮正常功能,就像“好孩子”那樣乖乖地呆在核里面,一旦被“教壞”了,就跑到核外面,引導(dǎo)癌細(xì)胞長大。張曉坤課題組最終找到可以對付這種癌蛋白的“K-80003”分子,他比喻說,“K-80003”能在這類癌蛋白要“叛變”時(shí),把它控制住,還要把它“教”好。

      去年,張曉坤決定全心回到廈大,最重要的原因是廈大要成立藥學(xué)院,他被任命為藥學(xué)院院長。張曉坤說,每次我們在實(shí)驗(yàn)室完成成果,大家都在問有沒有用,所以,你需要一些平臺,把這些成果變成現(xiàn)實(shí),藥學(xué)院便是這樣一個(gè)平臺。

      文章來源:《廈門日報(bào)》2011-03-23

      媒體報(bào)道三:


      青年科學(xué)家張曉坤: 發(fā)現(xiàn)癌細(xì)胞克星

      近日,廈門大學(xué)生物醫(yī)學(xué)研究院的科學(xué)家們發(fā)現(xiàn)了一種名為“K-80003”的新型抗癌藥物分子,當(dāng)它作用于癌細(xì)胞中的特異靶點(diǎn)——“tRXRα”蛋白時(shí),不但能夠抑制癌細(xì)胞的生長,還能激活體內(nèi)其他細(xì)胞因子殺滅癌細(xì)胞。這一研究成果發(fā)表在了國際期刊《癌細(xì)胞》雜志上。

      《北京科技報(bào)》:什么是癌細(xì)胞中的特異靶點(diǎn),為什么科學(xué)家想要找到它們?

      張曉坤:人體細(xì)胞中存在多種蛋白,癌細(xì)胞也不例外。有一些僅存于癌細(xì)胞、而不存在于正常細(xì)胞中的癌蛋白,對癌細(xì)胞的生長起著很關(guān)鍵的作用,如果合理調(diào)控它們,就可以控制癌細(xì)胞的生長與死亡。這樣的癌蛋白就被稱為特異靶點(diǎn)。

      科學(xué)家想要找到這些特異靶點(diǎn),從而研究出具有針對性的癌癥診斷、治療方法。尤其是靶點(diǎn)藥,相較于好、壞細(xì)胞通殺的一般化療藥物,它更加安全、有效,因此,也成為當(dāng)今世界上抗癌藥物發(fā)展的方向和未來個(gè)性化治療的重要基礎(chǔ)。

      《北京科技報(bào)》:“tRXRα”蛋白是一種怎樣的靶分子?

      張曉坤:“tRXRα”蛋白是在正常細(xì)胞向癌細(xì)胞變化過程中產(chǎn)生的一種癌蛋白。在癌變過程中,正常的RXRα蛋白被剪切成了tRXRα癌蛋白。正常的RXRα蛋白是調(diào)控人體重要生物學(xué)功能的關(guān)鍵蛋白,而tRXRα癌蛋白卻是對癌細(xì)胞的生長起著推動(dòng)作用的“壞蛋白”。

      盡管如此,“壞蛋白”能夠指示細(xì)胞是否癌化,有希望成為個(gè)體診斷的標(biāo)記分子,在預(yù)防和診斷癌癥中發(fā)揮作用,而開發(fā)“壞蛋白”靶向藥物還能達(dá)到針對性地作用于癌細(xì)胞的完美效果。

      《北京科技報(bào)》:針對“tRXRα”靶分子的新型抗癌藥物分子——“K-80003”是如何被發(fā)現(xiàn)的?

      張曉坤:其實(shí),我們最先進(jìn)行廣泛篩選后找到了一種名為“舒林酸”的消炎止痛藥,它可以抑制tRXRα癌蛋白的活性,但同時(shí)也會對人體的消化道和心血管造成嚴(yán)重的毒副作用。

      于是,我們用計(jì)算機(jī)模擬的方法,針對tRXRα的蛋白結(jié)構(gòu)、結(jié)合靶位等生化特點(diǎn),重新創(chuàng)造了“K-80003”,應(yīng)該說它是舒林酸的優(yōu)化產(chǎn)物。一方面K-80003不再抑制細(xì)胞正常功能所需的COX蛋白的活性,毒副作用大大降低;另一方面,它能夠更好地結(jié)合tRXRα癌蛋白,抑制腫瘤生長的作用遠(yuǎn)遠(yuǎn)大于舒林酸。

      《北京科技報(bào)》:這個(gè)發(fā)現(xiàn)將如何轉(zhuǎn)化為實(shí)際應(yīng)用?

      張曉坤:這項(xiàng)發(fā)現(xiàn)無論在癌癥的病理研究還是臨床診斷和治療上,都具有非常深遠(yuǎn)的理論意義和廣泛的應(yīng)用前景。目前,我們正在進(jìn)行成果轉(zhuǎn)化方面的進(jìn)一步研究,力爭一兩年內(nèi)完成含有K-80003抗癌分子的靶點(diǎn)藥的臨床前研究,從而轉(zhuǎn)入臨床試驗(yàn),希望能早日造福癌癥患者。

      文章來源:《北京科技報(bào)》2010-7-23

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