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Sox2

维基百科,自由的百科全书

SRY-box transcription factor 2
识别号
别名;SOX2、​SRY (sex determining region Y)-box 2、​SRY-box 2、​SRY-related HMG-box gene 2、​sex determining region Y-box 2、​transcription factor SOX-2、​transcription factor SOX2
外部IDGeneCards[1]
直系同源
物种人类小鼠
Entrez
Ensembl
UniProt
mRNA​序列

n/a

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蛋白序列

n/a

n/a

基因位置​(UCSC)n/an/a
PubMed​查找n/an/a
维基数据
检视/编辑 人类

SRY盒-2(SRY:性别决定区,Sex Determining Region Y),又称“Sox2”(人的Sox2应写为SOX2),是一种对未分化的胚胎干细胞(ESC)、神经干细胞等再生能力以及多能性维持至关重要转录因子[1]。对Sox2的研究对干细胞生物学、再生医学的发展有重要意义[2]

Sox2隶属于Sox转录因子家族。Sox转录因子家族在哺乳动物的发育过程中扮演重要角色。该家族的蛋白质都有一个保守的DNA结合结构域,长约80个氨基酸残基,称为HMG英语高遷移律組(High-mobility group,高迁移律组)盒结构域[1]

功能

干性维持

白血病抑制因子(LIF)能通过激活Sox2调控的下游,诸如JAK-STAT信号通路,继而激活Klf4英语Klf4Kruppel样因子英语Kruppel-like factors家族下的一种蛋白质)的表达,以维持胚胎干细胞的干性。Oct4、Sox2以及Nanog能增强所有LIF调控的通路相关的蛋白质的表达[3]

Npm1英语Npm1是一种与细胞增殖相关的转录调节蛋白,在胚胎干细胞中能与Sox2、Oct4、Nanog形成蛋白复合物[4]。Sox2、Oct4、Nanog三个转录因子共同组成了一个与多能性维持相关的转录调控网络。Sox2能与Oct4一同与DNA非回文序列结合,以激活与多能性维持的关键因子转录[5]。令人惊讶的是,对Oct4-Sox2增强子的调控即使没有Sox2也可以发生,可能是因为其他Sox家族的蛋白质的表达。不过,已有研究人员确认Sox2在胚胎干细胞干性维持中的主要作用是控制Oct4的表达。另外,Oct4、Sox2一旦表达,就会自我维持持续表达的状态[6]

向体细胞中转入Sox2加上Oct4、c-Myc、Klf4四个因子的基因就可以诱导iPSC的产生[7]

一些Sox2、Oct4的结合位点的高甲基化以及miR134对Sox2的转录后抑制调控男性生殖细胞多能性丢失[8][9]

Sox2不同的表达水平决定了胚胎干细胞的分化命运。Sox2能抑制胚胎干细胞分化为中胚层、内胚层的细胞,并能促进其分化为外胚层的神经细胞[10]。在细胞分化为外胚层系细胞的过程中,Npm1/Sox2复合物能持续表达,说明Sox2在外胚层分化过程中发挥的重要作用[4]

通过对基因敲除鼠的研究,已证明Sox2表达的缺失会使神经畸形,对胚胎是致死的。进一步说明Sox2对胚胎发育的重要性[11]

神经干细胞

神经发生过程中,Sox2在神经管细胞以及中枢神经系统祖细胞增殖过程中会表达。然而,在祖细胞退出细胞周期,进入G0期的过程中,Sox2的表达会下调[12]。细胞表达Sox2能促进细胞增殖,也能促进细胞分化为神经细胞,而细胞增殖和分化的能力正是干细胞的两个最显著的特征。表达Sox2的(Sox2+)神经干细胞能进行细胞分裂,产生与其相同的Sox2+神经干细胞,同时还能产生神经细胞前体细胞[13]

使用成体神经干细胞(其Sox2以及c-Myc的表达水平高于胚胎干细胞),只需要转入两种因子(其中一个必须是Oct4)就足以产生诱导多能性干细胞,减少了转入多个因子时可能产生的风险以及副作用[14]

眼畸形

SOX2基因突变与双眼眼球炎,一种严重的结构性眼畸形有关[15]

癌症

在肺发育过程中,Sox2控制支气管分支的形态发生以及空气通道上皮的分化[16]。在通常情况下,Sox2对气管上皮的基底细胞的自我更新以及比例维持至关重要。然而,Sox2的过表达会造成上皮增生,并最终在发育中以及成体小鼠体内诱发肺部癌变[17]

鳞状细胞癌中,常常可以检出3q26.3区基因的扩增。Sox2基因即位于该区域,说明Sox2是一种原癌基因。Sox2能诱发鳞状细胞癌,激活许多与肿瘤发生相关的基因表达。Sox2的过表达与Lkb1的不表达能促进小鼠肺部鳞状上皮细胞的癌变[18]。Sox2的过表达也可以激活细胞的迁移以及锚定非依赖性生长[19]

Sox2表达与高格里森分级英语gleason grade的前列腺癌有关,能促进去势抵抗性前列腺癌的生长[20]

SOX2的别构表达与结直肠癌中的细胞异常分化有关[21]。另外,Sox2与乳腺癌对他莫昔芬的抗性有关[22]

甲状腺激素的调控

Sox2启动子的上游(即增强子区域)有三个甲状腺激素应答元件(TRE),甲状腺激素(T3)能通过这些区域下调Sox2的表达。在神经干细胞的增殖迁移过程中,TRα1(一种甲状腺激素的受体)的表达会上调。此现象提示甲状腺激素能通过甲状腺激素信号通路对Sox2进行转录抑制,促进神经干细胞从脑室下区迁出并分化。人胚胎发育过程中甲状腺激素的缺失,尤其是胚胎发育的头三个月中的缺失,会造成中枢神经系统发育的异常。因此,可以得出结论,在胚胎发育中,甲状腺激素水平低会造成神经性缺陷,诸如以发育不良为特征的呆小症[23]

相互作用

Sox2能与Pax6英语Pax6、NPM1、Oct4之间发生相互作用[24][3][5]。已证明Sox2能与Oct3/4协同调控Rex1英语Rex1的表达[25]

参考

  1. ^ 1.0 1.1 SOX2. NCBI. (原始内容存档于2016-01-05). 
  2. ^ Rizzino A. Sox2 and Oct-3/4: a versatile pair of master regulators that orchestrate the self-renewal and pluripotency of embryonic stem cells. Wiley Interdisciplinary Reviews. Systems Biology and Medicine. 2009, 1 (2): 228–36. PMC 2794141. PMID 20016762. doi:10.1002/wsbm.12. 
  3. ^ 3.0 3.1 Niwa H, Ogawa K, Shimosato D, Adachi K. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. July 2009, 460 (7251): 118–22. PMID 19571885. doi:10.1038/nature08113. 
  4. ^ 4.0 4.1 Johansson H, Simonsson S. Core transcription factors, Oct4, Sox2 and Nanog, individually form complexes with nucleophosmin (Npm1) to control embryonic stem (ES) cell fate determination. Aging. November 2010, 2 (11): 815–22. PMC 3006024. PMID 21076177. doi:10.18632/aging.100222. 
  5. ^ 5.0 5.1 Chambers I, Tomlinson SR. The transcriptional foundation of pluripotency. Development. July 2009, 136 (14): 2311–22. PMC 2729344. PMID 19542351. doi:10.1242/dev.024398. 
  6. ^ Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov AA, Ko MS, Niwa H. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nature Cell Biology. June 2007, 9 (6): 625–35. PMID 17515932. doi:10.1038/ncb1589. 
  7. ^ Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. August 2006, 126 (4): 663–76. PMID 16904174. doi:10.1016/j.cell.2006.07.024. 
  8. ^ Imamura M, Miura K, Iwabuchi K, Ichisaka T, Nakagawa M, Lee J, Kanatsu-Shinohara M, Shinohara T, Yamanaka S. Transcriptional repression and DNA hypermethylation of a small set of ES cell marker genes in male germline stem cells. BMC Developmental Biology. 2006, 6: 34. PMC 1564388. PMID 16859545. doi:10.1186/1471-213X-6-34. 
  9. ^ Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature. October 2008, 455 (7216): 1124–8. PMID 18806776. doi:10.1038/nature07299. 
  10. ^ Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S. Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell. June 2011, 145 (6): 875–89. PMID 21663792. doi:10.1016/j.cell.2011.05.017. 
  11. ^ Ferri AL, Cavallaro M, Braida D, Di Cristofano A, Canta A, Vezzani A, Ottolenghi S, Pandolfi PP, Sala M, DeBiasi S, Nicolis SK. Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development. August 2004, 131 (15): 3805–19. PMID 15240551. doi:10.1242/dev.01204. 
  12. ^ Graham V, Khudyakov J, Ellis P, Pevny L. SOX2 functions to maintain neural progenitor identity. Neuron. August 2003, 39 (5): 749–65. PMID 12948443. doi:10.1016/S0896-6273(03)00497-5. 
  13. ^ Suh H, Consiglio A, Ray J, Sawai T, D'Amour KA, Gage FH. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell. November 2007, 1 (5): 515–28. PMC 2185820. PMID 18371391. doi:10.1016/j.stem.2007.09.002. 
  14. ^ Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature. July 2008, 454 (7204): 646–50. PMID 18594515. doi:10.1038/nature07061. 
  15. ^ Entrez Gene: SOX2 SRY (sex determining region Y)-box 2. (原始内容存档于2010-04-13). 
  16. ^ Gontan C, de Munck A, Vermeij M, Grosveld F, Tibboel D, Rottier R. Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Developmental Biology. May 2008, 317 (1): 296–309. PMID 18374910. doi:10.1016/j.ydbio.2008.02.035. 
  17. ^ Lu Y, Futtner C, Rock JR, Xu X, Whitworth W, Hogan BL, Onaitis MW. Evidence that SOX2 overexpression is oncogenic in the lung. PLoS ONE. 2010, 5 (6): e11022. PMC 2883553. PMID 20548776. doi:10.1371/journal.pone.0011022. 
  18. ^ Mukhopadhyay A, Berrett KC, Kc U, Clair PM, Pop SM, Carr SR, Witt BL, Oliver TG. Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Reports. July 2014, 8 (1): 40–9. PMID 24953650. doi:10.1016/j.celrep.2014.05.036. 
  19. ^ Hussenet T, Dali S, Exinger J, Monga B, Jost B, Dembelé D, Martinet N, Thibault C, Huelsken J, Brambilla E, du Manoir S. SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS ONE. 2010, 5 (1): e8960. PMC 2813300. PMID 20126410. doi:10.1371/journal.pone.0008960. 
  20. ^ Kregel S, Kiriluk KJ, Rosen AM, Cai Y, Reyes EE, Otto KB, Tom W, Paner GP, Szmulewitz RZ, Vander Griend DJ. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer. PLoS ONE. 2013, 8 (1): e53701. PMC 3543364. PMID 23326489. doi:10.1371/journal.pone.0053701. 
  21. ^ Tani Y, Akiyama Y, Fukamachi H, Yanagihara K, Yuasa Y. Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression. Journal of Cancer Research and Clinical Oncology. April 2007, 133 (4): 263–9. PMID 17136346. doi:10.1007/s00432-006-0165-x. 
  22. ^ Piva M, Domenici G, Iriondo O, Rábano M, Simões BM, Comaills V, Barredo I, López-Ruiz JA, Zabalza I, Kypta R, Vivanco Md. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Molecular Medicine. January 2014, 6 (1): 66–79. PMC 3936493. PMID 24178749. doi:10.1002/emmm.201303411. 
  23. ^ López-Juárez A, Remaud S, Hassani Z, Jolivet P, Pierre Simons J, Sontag T, Yoshikawa K, Price J, Morvan-Dubois G, Demeneix BA. Thyroid hormone signaling acts as a neurogenic switch by repressing Sox2 in the adult neural stem cell niche. Cell Stem Cell. May 2012, 10 (5): 531–43. PMID 22560077. doi:10.1016/j.stem.2012.04.008. 
  24. ^ Aota S, Nakajima N, Sakamoto R, Watanabe S, Ibaraki N, Okazaki K. Pax6 autoregulation mediated by direct interaction of Pax6 protein with the head surface ectoderm-specific enhancer of the mouse Pax6 gene. Developmental Biology. May 2003, 257 (1): 1–13. PMID 12710953. doi:10.1016/S0012-1606(03)00058-7. 
  25. ^ Shi W, Wang H, Pan G, Geng Y, Guo Y, Pei D. Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. Journal of Biological Chemistry. August 2006, 281 (33): 23319–25. PMID 16714766. doi:10.1074/jbc.M601811200. 

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