SOX2

Sox2
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	1O4X、2LE4
識別號
别名	SOX2；, ANOP3, MCOPS3, SRY-box 2, Sox2, SRY-box transcription factor 2
外部ID	OMIM：184429 MGI：98364 HomoloGene：68298 GeneCards：SOX2
相關疾病
	syndromic microphthalmia 3
基因位置（人类）
染色体	3號染色體
终止	181,714,436 bp
基因位置（小鼠）
染色体	小鼠3号染色体
终止	34,706,610 bp
RNA表达模式
	; ;
	查阅更多表达数据
基因本體
分子功能	• DNA结合; • sequence-specific DNA binding; • miRNA binding; • DNA结合转录因子活性; • DNA-binding transcription activator activity, RNA polymerase II-specific; • transcription cis-regulatory region binding; • 血浆蛋白结合; • DNA-binding transcription factor activity, RNA polymerase II-specific;
細胞組分	• 細胞質; • 细胞质基质; • 轉錄調節複合物; • 核质; • 细胞核;
生物學過程	• 眼部發展; • 垂体的发生; • regulation of transcription, DNA-templated; • negative regulation of neuron differentiation; • somatic stem cell population maintenance; • endodermal cell fate specification; • positive regulation of cell-cell adhesion; • tissue regeneration; • negative regulation of transcription by RNA polymerase II; • chromatin organization; • transcription by RNA polymerase II; • regulation of cysteine-type endopeptidase activity involved in apoptotic process; • adenohypophysis development; • transcription, DNA-templated; • neuronal stem cell population maintenance; • positive regulation of transcription, DNA-templated; • multicellular organism development; • glial cell fate commitment; • response to wounding; • osteoblast differentiation; • positive regulation of cell differentiation; • negative regulation of epithelial cell proliferation; • 基因調節; • 内耳的发生; • forebrain development; • response to growth factor; • negative regulation of canonical Wnt signaling pathway; • positive regulation of MAPK cascade; • positive regulation of transcription by RNA polymerase II; • cytokine-mediated signaling pathway; • 细胞分化; • cell fate commitment; • central nervous system development; • neuron differentiation;
	Sources:Amigo / QuickGO
直系同源
	6657
	20674
	ENSG00000181449
	ENSMUSG00000074637
	P48431
	P48432
	NM_003106
	NM_011443
	NP_003097
	NP_035573
	維基數據
檢視/編輯人類	檢視/編輯小鼠

SRY盒-2（SRY：性別決定區，Sex Determining Region Y），又稱「Sox2」（人的Sox2應寫爲SOX2），是一種對未分化的胚胎幹細胞（ESC）、神經幹細胞等再生能力以及多能性維持至關重要轉錄因子^[6]。對Sox2的研究對幹細胞生物學、再生醫學的發展有重要意義^[7]。

Sox2隸屬於SOX 轉錄因子家族。Sox轉錄因子家族在哺乳動物的發育過程中扮演重要角色。該家族的蛋白質都有一個保守的DNA結合結構域，長約80個氨基酸殘基，稱爲高迁移率组（High-mobility group，HMG）盒結構域^[6]。

功能

幹性維持

白血病抑制因子（LIF）能通過激活Sox2調控的下游，諸如JAK-STAT信號通路，繼而激活Klf4（Kruppel樣因子家族下的一種蛋白質）的表達，以維持胚胎幹細胞的幹性。Oct4、Sox2以及Nanog能增強所有LIF調控的通路相關的蛋白質的表達^[8]。

Npm1（英语：Npm1）是一種與細胞增殖相關的轉錄調節蛋白，在胚胎幹細胞中能與Sox2、Oct4、Nanog形成蛋白複合物^[9]。Sox2、Oct4、Nanog三個轉錄因子共同組成了一個與多能性維持相關的轉錄調控網絡。Sox2能與Oct4一同與DNA非回文序列結合，以激活與多能性維持的關鍵因子轉錄^[10]。令人驚訝的是，對Oct4-Sox2增強子的調控即使沒有Sox2也可以發生，可能是因爲其他Sox家族的蛋白質的表達。不過，已有研究人員確認Sox2在胚胎幹細胞幹性維持中的主要作用是控制Oct4的表達。另外，Oct4、Sox2一旦表達，就會自我維持持續表達的狀態^[11]。

向體細胞中轉入Sox2加上Oct4、c-Myc、Klf4四個因子的基因就可以誘導iPSC的產生^[12]。

一些Sox2、Oct4的結合位點的高甲基化以及miR134對Sox2的轉錄後抑制調控男性生殖細胞多能性丟失^[13]^[14]。

Sox2不同的表達水平決定了胚胎幹細胞的分化命運。Sox2能抑制胚胎幹細胞分化爲中胚層、內胚層的細胞，並能促進其分化爲外胚層的神經細胞^[15]。在細胞分化爲外胚層系細胞的過程中，Npm1/Sox2複合物能持續表達，說明Sox2在外胚層分化過程中發揮的重要作用^[9]。

通過對基因敲除鼠的研究，已證明Sox2表達的缺失會使神經畸形，對胚胎是致死的。進一步說明Sox2對胚胎發育的重要性^[16]。

神經幹細胞

神經發生過程中，Sox2在神經管細胞以及中樞神經系統祖細胞增殖過程中會表達。然而，在祖細胞退出細胞週期，進入G0期的過程中，Sox2的表達會下調^[17]。細胞表達Sox2能促進細胞增殖，也能促進細胞分化爲神經細胞，而細胞增殖和分化的能力正是幹細胞的兩個最顯著的特徵。表達Sox2的（Sox2+）神經幹細胞能進行細胞分裂，產生與其相同的Sox2+神經幹細胞，同時還能產生神經細胞前體細胞^[18]。

使用成體神經幹細胞（其Sox2以及c-Myc的表達水平高於胚胎幹細胞），只需要轉入兩種因子（其中一個必須是Oct4）就足以產生誘導多能性幹細胞，減少了轉入多個因子時可能產生的風險以及副作用^[19]。

眼畸形

人SOX2基因突變與双眼眼球炎，一種嚴重的結構性眼畸形有關^[20]。

癌症

在肺發育過程中，Sox2控制支氣管分支的形態發生以及空氣通道上皮的分化^[21]。在通常情況下，Sox2對氣管上皮的基底細胞的自我更新以及比例維持至關重要。然而，Sox2的過表達會造成上皮增生，並最終在發育中以及成體小鼠體內誘發肺部癌變^[22]。

鳞状细胞癌中，常常可以檢出3q26.3區基因的擴增。Sox2基因即位於該區域，說明Sox2是一種原癌基因。Sox2能誘發鱗狀細胞癌，激活許多與腫瘤發生相關的基因表達。Sox2的過表達與Lkb1的不表達能促進小鼠肺部鱗狀上皮細胞的癌變^[23]。Sox2的過表達也可以激活細胞的遷移以及錨定非依賴性生長^[24]。

Sox2表達與高格里森分级（英语：gleason grade）的前列腺癌有關，能促進去势抵抗性前列腺癌的生長^[25]。

SOX2的異位表達與結直腸癌中的細胞異常分化有關^[26]。另外，Sox2與乳腺癌對他莫昔芬的抗性有關^[27]。

甲狀腺激素的調控

Sox2啓動子的上游（即增強子區域）有三個甲狀腺激素應答元件（TRE），甲狀腺激素（T3）能通過這些區域下調Sox2的表達。在神經幹細胞的增殖遷移過程中，TRα1（一種甲狀腺激素的受體）的表達會上調。此現象提示甲狀腺激素能通過甲狀腺激素信號通路對Sox2進行轉錄抑制，促進神經幹細胞從腦室下區遷出並分化。人胚胎發育過程中甲狀腺激素的缺失，尤其是胚胎發育的頭三個月中的缺失，會造成中樞神經系統發育的異常。因此，可以得出結論，在胚胎發育中，甲狀腺激素水平低會造成神經性缺陷，諸如以發育不良爲特徵的呆小症^[28]。

相互作用

Sox2能與Pax6（英语：Pax6）、NPM1、Oct4之間發生相互作用^[29]^[8]^[10]。已證明Sox2能與Oct3/4協同調控Rex1（英语：Rex1）的表達^[30]。

參考

^ 與Sox2相關的疾病；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000181449 - Ensembl, May 2017
^ ^3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000074637 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^6.0 ^6.1 SOX2. NCBI. （原始内容存档于2016-01-05）.
^ 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.
^ ^8.0 ^8.1 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.
^ ^9.0 ^9.1 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.
^ ^10.0 ^10.1 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Entrez Gene: SOX2 SRY (sex determining region Y)-box 2. （原始内容存档于2010-04-13）.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

拓展閱讀

Kamachi Y, Uchikawa M, Kondoh H. Pairing SOX off: with partners in the regulation of embryonic development. Trends in Genetics. April 2000, 16 (4): 182–7. PMID 10729834. doi:10.1016/S0168-9525(99)01955-1.
Schepers GE, Teasdale RD, Koopman P. Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Developmental Cell. August 2002, 3 (2): 167–70. PMID 12194848. doi:10.1016/S1534-5807(02)00223-X.
Hever AM, Williamson KA, van Heyningen V. Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Clinical Genetics. June 2006, 69 (6): 459–70. PMID 16712695. doi:10.1111/j.1399-0004.2006.00619.x.
Yuan H, Corbi N, Basilico C, Dailey L. Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes & Development. November 1995, 9 (21): 2635–45. PMID 7590241. doi:10.1101/gad.9.21.2635.
Stevanovic M, Zuffardi O, Collignon J, Lovell-Badge R, Goodfellow P. The cDNA sequence and chromosomal location of the human SOX2 gene. Mammalian Genome. October 1994, 5 (10): 640–2. PMID 7849401. doi:10.1007/BF00411460.
Bonaldo MF, Lennon G, Soares MB. Normalization and subtraction: two approaches to facilitate gene discovery. Genome Research. September 1996, 6 (9): 791–806. PMID 8889548. doi:10.1101/gr.6.9.791.
Helland R, Berglund GI, Otlewski J, Apostoluk W, Andersen OA, Willassen NP, Smalås AO. High-resolution structures of three new trypsin-squash-inhibitor complexes: a detailed comparison with other trypsins and their complexes. Acta Crystallographica Section D. January 1999, 55 (Pt 1): 139–48. PMID 10089404. doi:10.1107/S090744499801052X.
Güre AO, Stockert E, Scanlan MJ, Keresztes RS, Jäger D, Altorki NK, Old LJ, Chen YT. Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer. Proceedings of the National Academy of Sciences of the United States of America. April 2000, 97 (8): 4198–203. PMC 18195  . PMID 10760287. doi:10.1073/pnas.97.8.4198.
Ambrosetti DC, Schöler HR, Dailey L, Basilico C. Modulation of the activity of multiple transcriptional activation domains by the DNA binding domains mediates the synergistic action of Sox2 and Oct-3 on the fibroblast growth factor-4 enhancer. The Journal of Biological Chemistry. July 2000, 275 (30): 23387–97. PMID 10801796. doi:10.1074/jbc.M000932200.
Kamachi Y, Uchikawa M, Tanouchi A, Sekido R, Kondoh H. Pax6 and SOX2 form a co-DNA-binding partner complex that regulates initiation of lens development. Genes & Development. May 2001, 15 (10): 1272–86. PMC 313803  . PMID 11358870. doi:10.1101/gad.887101.
Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, Hayward C, Vivian AJ, Williamson K, van Heyningen V, FitzPatrick DR. Mutations in SOX2 cause anophthalmia. Nature Genetics. April 2003, 33 (4): 461–3. PMID 12612584. doi:10.1038/ng1120.
Wiebe MS, Nowling TK, Rizzino A. Identification of novel domains within Sox-2 and Sox-11 involved in autoinhibition of DNA binding and partnership specificity. Journal of Biological Chemistry. May 2003, 278 (20): 17901–11. PMID 12637543. doi:10.1074/jbc.M212211200.
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.
Schepers G, Wilson M, Wilhelm D, Koopman P. SOX8 is expressed during testis differentiation in mice and synergizes with SF1 to activate the Amh promoter in vitro. Journal of Biological Chemistry. July 2003, 278 (30): 28101–8. PMID 12732652. doi:10.1074/jbc.M304067200.
Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M. Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers. Genes & Development. August 2003, 17 (16): 2048–59. PMC 196258  . PMID 12923055. doi:10.1101/gad.269303.
Williams DC, Cai M, Clore GM. Molecular basis for synergistic transcriptional activation by Oct1 and Sox2 revealed from the solution structure of the 42-kDa Oct1.Sox2.Hoxb1-DNA ternary transcription factor complex. Journal of Biological Chemistry. January 2004, 279 (2): 1449–57. PMID 14559893. doi:10.1074/jbc.M309790200.
Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. Journal of Cancer Research and Clinical Oncology. March 2004, 130 (3): 135–45. PMID 14655050. doi:10.1007/s00432-003-0519-6.

外部連結

[1] 與Sox2相關的疾病；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] 2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000181449 - Ensembl, May 2017

[refGRCm38Ensembl-3] 3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000074637 - Ensembl, May 2017

[4] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[:0-6] 6.0 ^6.1 SOX2. NCBI. （原始内容存档于2016-01-05）.

[pmid20016762-7] 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.

[pmid19571885-8] 8.0 ^8.1 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.

[pmid21076177-9] 9.0 ^9.1 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.

[Chambers_Tomlinson_2009-10] 10.0 ^10.1 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.

[pmid17515932-11] 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.

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