第4期 营孙阳等：端粒酶调控研究进展 297 lear receptors.Cell,2015,160(5):811-813. 4展望 [5]Ly H.Genetic and environmental factors influencing hu- 对端粒酶的深入研究逐渐揭示了肿瘤细胞的端 man diseases with telomere dysfunction.Clin Exp Med, 2009,2(2:114-130 粒酶活性与细胞衰老之间的联系，如正常细胞可以 [6]Fu D,Collins K.Purification of human telomerase com- 通过遗传操作转入TERT亚基使其获得端粒酶活性 plexes identifies factors involved in telomerase biogenesis 而发生永生化逃避衰老等。近期关于端粒酶的研究 and telomere length regulation.Mol Cell,2007, 逐渐揭示了辅助蛋白在维持端粒酶复合体活性和功 28(5773-785. 能方面的重要作用，对这些辅助蛋白的深入研究开 [7]Venteicher AS,Meng ZJ,Mason PJ,Veenstra TD,Artandi SE.Identification of ATPases pontin and reptin as telo- 创了靶向端粒酶辅助蛋白而间接抑制端粒酶活性治 merase components essential for holoenzyme assembly 疗癌症的新方法。总之，端粒酶活性的调节包含多 Cell,2008.132(6:945-957. 个调控因素：TERT水平的调控、转录后修饰、运输、 [8]Zhong F,Savage SA,Shkreli M,Giri N,Jessop L,MyersT, 定位、最终构象的调控以及在端粒酶复合体装配过 Chen R,Alter BP,Artandi SE.Disruption of telomerase 程中与辅助蛋白的相互作用的调控，这些端粒酶调 trafficking by TCABI mutation causes dyskeratosis con- 控研究为癌症的治疗提供了许多值得探索的重要靶 genita.Gene Dev,2011,25(1):11-16. [9]Trochet D,Mergui X,Ivkovic I,Porreca RM,Ger- 标。目前端粒酶调控的许多内容都已被详细的研究 bault-Seureau M,Sidibe A,Richard F,Londono-Vallejo A, 探讨，为进一步发现调控端粒酶活性的分子奠定了 Perret M,Aujard F,Riou JF.Telomere regulation during 基础s2。如伊美司他(Imetelstat)是一个合成分子， ageing and tumorigenesis of the grey mouse lemur.Bio- 在端粒酶的活性位点区域结合端粒酶RNA组分并 chimie,2015,113:100-110. 降低了端粒酶活性s3,54。姜黄素(Curcumin)被证明在 [10]Shay JW,Wright WE.Senescence and immortalization: role of telomeres and telomerase.Carcinogenesis,2005, 某些类型的癌症中可以抑制端粒酶活性，这种抑制 26(5):867-874. 可能是使从TERT上解离的HSP-90和p23伴侣蛋白 [11]Killela PJ,Reitman ZJ,Jiao YC,Bettegowda C,Agrawal 不能易位到细胞核s。莱菔硫烷(Sulforaphane)已经 N,Diaz LA,Jr.,Friedman AH,Friedman H,Gallia GL, 被证明可以导致TERT的表达水平和磷酸化水平降 Giovanella BC.Grollman AP.He TC.He YP.Hruban RH. 低，阻止了向细胞核的易位56。然而，鲜有证据表 Jallo GI,Mandahl N,Meeker AK,Mertens F,Netto GJ, Ahmed Rasheed B,Riggins GJ,Rosenquist TA,Schiffman 明我们可以通过靶问Dyskerin、GAR1、Nopl0和 M,Shih IM,Theodorescu D,Torbenson MS,Velculescu NHP2等端粒酶复合体的其他组分而改变端粒酶活 VE,Wang TL,Wentzensen N,Wood LD,Zhang M, 性，这些问题在间接应用抗端粒治疗癌症的道路上 McLendon RE,Bigner DD,Kinzler KW,Vogelstein B. 给我们留下了探索的机会5。 Papadopoulos N,Yan H.TERT promoter mutations occur frequently in gliomas and a subset of tumors derived 参考文献(References): from cells with low rates of self-renewal.Proc Natl Acad Sci USA,2013,110(15:6021-6026. [1]Palm W,de Lange T.How shelterin protects mammalian [12]Horn S,Figl A,Sivaramakrishna Rachakonda P,Fischer C, telomeres.Annu Rey Genet,2008,42:301-334 Sucker A,Gast A,Kadel S,Moll I,Nagore E,Hemminki [2]O'Sullivan RJ,Karlseder J.Telomeres:protecting chro- K,Schadendorf D,Kumar R.TERT promoter mutations in mosomes against genome instability.Nat Rey Mol Cell familial and sporadic melanoma.Science,2013,339(6122): Biol,2010,11(3:171-181. 959-961. [3]Kabir S,Hockemeyer D,de Lange T.TALEN gene [13]Kyo S,Takakura M,Fujiwara T,Inoue M.Understanding knockouts reveal no requirement for the conserved human and exploiting hTERT promoter regulation for diagnosis shelterin protein Rapl in telomere protection and length and treatment of human cancers.Cancer Sci,2008,99(8): regulation.Cell Rep,2014,9(4):1273-1280. 1528-1538. [4]Aeby E,Lingner J.ALT telomeres get together with nuc- [14]Greenberg RA.Telomeres,crisis and cancer.Curr Mol ?1994-2016 China Academic Journal Electronic Publishing House.All rights reserved.http://www.cnki.net第 4 期 营孙阳等: 端粒酶调控研究进展 297 4 展 望 对端粒酶的深入研究逐渐揭示了肿瘤细胞的端 粒酶活性与细胞衰老之间的联系，如正常细胞可以 通过遗传操作转入 TERT 亚基使其获得端粒酶活性 而发生永生化逃避衰老等。近期关于端粒酶的研究 逐渐揭示了辅助蛋白在维持端粒酶复合体活性和功 能方面的重要作用，对这些辅助蛋白的深入研究开 创了靶向端粒酶辅助蛋白而间接抑制端粒酶活性治 疗癌症的新方法。总之，端粒酶活性的调节包含多 个调控因素：TERT 水平的调控、转录后修饰、运输、 定位、最终构象的调控以及在端粒酶复合体装配过 程中与辅助蛋白的相互作用的调控，这些端粒酶调 控研究为癌症的治疗提供了许多值得探索的重要靶 标。目前端粒酶调控的许多内容都已被详细的研究 探讨，为进一步发现调控端粒酶活性的分子奠定了 基础[52]。如伊美司他(Imetelstat)是一个合成分子， 在端粒酶的活性位点区域结合端粒酶 RNA 组分并 降低了端粒酶活性[53,54]。姜黄素(Curcumin)被证明在 某些类型的癌症中可以抑制端粒酶活性，这种抑制 可能是使从 TERT 上解离的 HSP-90 和 p23 伴侣蛋白 不能易位到细胞核[55]。莱菔硫烷(Sulforaphane)已经 被证明可以导致 TERT 的表达水平和磷酸化水平降 低，阻止了向细胞核的易位[56]。然而，鲜有证据表 明我们可以通过靶向 Dyskerin、GAR1、Nop10 和 NHP2 等端粒酶复合体的其他组分而改变端粒酶活 性，这些问题在间接应用抗端粒治疗癌症的道路上 给我们留下了探索的机会[57]。 参考文献(References)： [1] Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet, 2008, 42: 301–334. [2] O'Sullivan RJ, Karlseder J. Telomeres: protecting chro￾mosomes against genome instability. Nat Rev Mol Cell Biol, 2010, 11(3): 171–181. [3] Kabir S, Hockemeyer D, de Lange T. TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation. Cell Rep, 2014, 9(4): 1273–1280. [4] Aeby E, Lingner J. ALT telomeres get together with nuc￾lear receptors. Cell, 2015, 160(5): 811–813. [5] Ly H. Genetic and environmental factors influencing hu￾man diseases with telomere dysfunction. Clin Exp Med, 2009, 2(2): 114–130. [6] Fu D, Collins K. Purification of human telomerase com￾plexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol Cell, 2007, 28(5): 773–785. [7] Venteicher AS, Meng ZJ, Mason PJ, Veenstra TD, Artandi SE. Identification of ATPases pontin and reptin as telo￾merase components essential for holoenzyme assembly. Cell, 2008, 132(6): 945–957. [8] Zhong F, Savage SA, Shkreli M, Giri N, Jessop L, Myers T, Chen R, Alter BP, Artandi SE. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis con￾genita. Gene Dev, 2011, 25(1): 11–16. [9] Trochet D, Mergui X, Ivkovic I, Porreca RM, Ger￾bault-Seureau M, Sidibe A, Richard F, Londono-Vallejo A, Perret M, Aujard F, Riou JF. Telomere regulation during ageing and tumorigenesis of the grey mouse lemur. Bio￾chimie, 2015, 113: 100–110. [10] Shay JW, Wright WE. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis, 2005, 26(5): 867–874. [11] Killela PJ, Reitman ZJ, Jiao YC, Bettegowda C, Agrawal N, Diaz LA, Jr., Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He YP, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Ahmed Rasheed B, Riggins GJ, Rosenquist TA, Schiffman M, Shih IM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA, 2013, 110(15): 6021–6026. [12] Horn S, Figl A, Sivaramakrishna Rachakonda P, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R. TERT promoter mutations in familial and sporadic melanoma. Science, 2013, 339(6122): 959–961. [13] Kyo S, Takakura M, Fujiwara T, Inoue M. Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci, 2008, 99(8): 1528–1538. [14] Greenberg RA. Telomeres, crisis and cancer. Curr Mol