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利用者:加藤勝憲/SOX9

An Error has occurred retrieving Wikidata item for infoboxAn Error has occurred retrieving Wikidata item for infobox転写因子SOX-9は、ヒトではSOX9遺伝子によってコードされているタンパク質である[1][2]。

Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.[1][2]

Function

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SOX-9は、HMG-boxクラスのDNA結合タンパク質の他のメンバーとともに、CCTTGAGという配列を認識する。増殖軟骨細胞に発現するが肥大軟骨細胞には発現せず、前駆細胞から軟骨細胞への分化に必須であり[3]、ステロイド生成因子1とともに抗ミュラーホルモン（AMH）遺伝子の転写を制御する[2]。

SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It is expressed by proliferating but not hypertrophic chondrocytes that is essential for differentiation of precursor cells into chondrocytes[3] and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.[2]

SOX-9はまた、男性の性的発達においても極めて重要な役割を果たしている。Sf1と協働することにより、SOX-9はセルトリ細胞でAMHを産生し、女性の生殖器官の形成を抑制することができる[4]。また、他のいくつかの遺伝子とも相互作用し、男性の性的器官の発達を促進する。このプロセスは、転写因子であるTestis determining factor（Y染色体の性決定領域SRYによってコードされる）が、遺伝子の上流にあるエンハンサー配列に結合することによって、SOX-9の活性を活性化することから始まる。SOX-9によるFGF9の活性化は、精巣索の形成やセルトリ細胞の増殖など、男性の発生における重要なプロセスを開始する。[7] 脳の発生では、Sox-9のマウスオルソログはWwp1、Wwp2、miR-140の発現を誘導し、新しく生まれた神経細胞の皮質板への進入を制御し、皮質ニューロンの軸索分岐と軸索形成を制御する[8]。

SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in Sertoli cells to inhibit the creation of a female reproductive system.[4] It also interacts with a few other genes to promote the development of male sexual organs. The process starts when the transcription factor Testis determining factor (encoded by the sex-determining region SRY of the Y chromosome) activates SOX-9 activity by binding to an enhancer sequence upstream of the gene.[5] Next, Sox9 activates FGF9 and forms feedforward loops with FGF9[6] and PGD2.[5] These loops are important for producing SOX-9; without these loops, SOX-9 would run out and the development of a female would almost certainly ensue. Activation of FGF9 by SOX-9 starts vital processes in male development, such as the creation of testis cords and the multiplication of Sertoli cells.[6] The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.[7] In the brain development, its murine ortholog Sox-9 induces the expression of Wwp1, Wwp2, and miR-140 to regulate cortical plate entry of newly born nerve cells, and regulate axon branching and axon formation in cortical neurons.[8]

SOX-9は、ヘッジホッグ経路と同様にノッチシグナル伝達経路の標的であり[9]、神経幹細胞の運命制御に関与している。In vivoおよびin vitroの研究から、SOX-9は神経新生を負に制御し、グリア形成と幹細胞の生存を正に制御することが示されている[10]。

SOX-9 is a target of the Notch signaling pathway, as well as the Hedgehog pathway, and plays a role in the regulation of neural stem cell fate. In vivo and in vitro studies show that SOX-9 negatively regulates neurogenesis and positively regulates gliogenesis and stem cell survival.

Clinical significance

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変異は、常染色体性逆転[2]や口蓋裂を伴うことが多い骨格奇形症候群カンポメリック異形成を引き起こす[11]。」

Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal[2] and cleft palate.[9]

SOX9はヒトでは17q24上の遺伝子砂漠に位置する。SOX9の両側にある転写単位から1Mb以上離れた高度に保存された非コード要素の欠失、転座による破壊、一点変異は、しばしば口蓋裂を伴うPierre Robin Sequenceと関連している[11][12]。

SOX9 sits in a gene desert on 17q24 in humans. Deletions, disruptions by translocation breakpoints and a single point mutation of highly conserved non-coding elements located > 1 Mb from the transcription unit on either side of SOX9 have been associated with Pierre Robin Sequence, often with a cleft palate.[9][10]

Sox9タンパク質は、複数の固形癌の発生と進行の両方に関与していることが示唆されている[13]。ヒトの発生過程における形態形成のマスターレギュレーターとしてのその役割は、悪性組織における撹乱の理想的な候補となる。具体的には、Sox9は前立腺癌[14]、大腸癌[15]、乳癌[16]などにおいて浸潤性と治療抵抗性を誘導し、致死的転移を促進するようである[17]。

The Sox9 protein has been implicated in both initiation and progression of multiple solid tumors.[11] Its role as a master regulator of morphogenesis during human development makes it an ideal candidate for perturbation in malignant tissues. Specifically, Sox9 appears to induce invasiveness and therapy-resistance in prostate,[12] colorectal,[13] breast[14] and other cancers, and therefore promotes lethal metastasis.[15] Many of these oncogenic effects of Sox9 appear dose dependent.[16][12][11]

SOX9 localisation and dynamics

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SOX9はほとんどが核に局在し、非常に移動しやすい。軟骨細胞株での研究から、SOX9の50％近くがDNAに結合しており、外部因子によって直接制御されていることが明らかになった。DNA上に存在する半減期は約14秒である[19]。

SOX9 is mostly localised in the nucleus and it is highly mobile. Studies in chondrocyte cell line has revealed nearly 50% of SOX9 is bound to DNA and it is directly regulated by external factors. Its half-time of residence on DNA is ~14 seconds.[17]

Role in sex reversal

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Sox9や関連遺伝子に変異があると、性転換や両性具有（ヒトではインターセクシュアル）を引き起こすことがある。Sox9によって活性化されるFgf9が存在しない場合、X染色体とY染色体の両方を持つ胎児は女性の生殖腺を発達させることができる[5]。

Mutations in Sox9 or any associated genes can cause reversal of sex and hermaphroditism (or intersexuality in humans). If Fgf9, which is activated by Sox9, is not present, a fetus with both X and Y chromosomes can develop female gonads;[5] the same is true if Dax1 is not present.[7] The related phenomena of hermaphroditism can be caused by unusual activity of the SRY, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells.[18]

Interactions

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SOX9はステロイド形成因子1、[4] MED12[21]、MAF[22]と相互作用することが示されている。

SOX9 has been shown to interact with Steroidogenic factor 1,[4] MED12[19] and MAF.[20]

See also

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  • SOX genes

Further reading

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References

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  1. ^ “Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1”. Nature Genetics 4 (2): 170–4. (June 1993). doi:10.1038/ng0693-170. PMID 83481556 
  2. ^ a b c “Entrez Gene: SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)”. 2023年7月5日閲覧。
  3. ^ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (2015). Robbins and Cotran pathologic basis of disease (Ninth ed.). p. 1182. ISBN 9780808924500 
  4. ^ a b “Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene”. Molecular and Cellular Biology 18 (11): 6653–65. (November 1998). doi:10.1128/mcb.18.11.6653. PMC 109250. PMID 9774680. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC109250/6 
  5. ^ a b c “The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation”. Development 136 (11): 1813–21. (June 2009). doi:10.1242/dev.032631. PMC 4075598. PMID 19429785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075598/6 
  6. ^ a b “Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination”. PLOS Biology 4 (6): e187. (June 2006). doi:10.1371/journal.pbio.0040187. PMC 1463023. PMID 16700629. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1463023/6 
  7. ^ a b “Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells”. Development 132 (13): 3045–54. (July 2005). doi:10.1242/dev.01890. PMID 15944188. 
  8. ^ “Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140”. Neuron 100 (5): 1097–1115.e15. (December 2018). doi:10.1016/j.neuron.2018.10.008. PMID 303928006 
  9. ^ a b “Cleft lip and palate: understanding genetic and environmental influences”. Nature Reviews. Genetics 12 (3): 167–78. (March 2011). doi:10.1038/nrg2933. PMC 3086810. PMID 21331089. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086810/. 
  10. ^ “Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence”. Nature Genetics 41 (3): 359–64. (March 2009). doi:10.1038/ng.329. PMID 192344736 
  11. ^ a b Jo, A; Denduluri, S; Zhang, B; Wang, Z; Yin, L; Yan, Z; Kang, R; Shi, LL et al. (December 2014). “The versatile functions of Sox9 in development, stem cells, and human diseases.”. Genes & Diseases 1 (2): 149–161. doi:10.1016/j.gendis.2014.09.004. PMC 4326072. PMID 25685828. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326072/. 
  12. ^ a b Nouri, M; Massah, S; Caradec, J; Lubik, AA; Li, N; Truong, S; Lee, AR; Fazli, L et al. (9 January 2020). “Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer.”. Clinical Cancer Research 26 (7): 1678–1689. doi:10.1158/1078-0432.CCR-19-0098. PMID 31919137. 
  13. ^ Prévostel, C; Blache, P (November 2017). “The dose-dependent effect of SOX9 and its incidence in colorectal cancer.”. European Journal of Cancer 86: 150–157. doi:10.1016/j.ejca.2017.08.037. PMID 28988015. 
  14. ^ Grimm, D; Bauer, J; Wise, P; Krüger, M; Simonsen, U; Wehland, M; Infanger, M; Corydon, TJ (23 March 2019). “The role of SOX family members in solid tumours and metastasis.”. Seminars in Cancer Biology 67 (Pt 1): 122–153. doi:10.1016/j.semcancer.2019.03.004. PMID 30914279. 
  15. ^ Aguilar-Medina, M; Avendaño-Félix, M; Lizárraga-Verdugo, E; Bermúdez, M; Romero-Quintana, JG; Ramos-Payan, R; Ruíz-García, E; López-Camarillo, C (2019). “SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer.”. Journal of Oncology 2019: 6754040. doi:10.1155/2019/6754040. PMC 6463569. PMID 31057614. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463569/. 
  16. ^ Yang, X; Liang, R; Liu, C; Liu, JA; Cheung, MPL; Liu, X; Man, OY; Guan, XY et al. (14 January 2019). “SOX9 is a dose-dependent metastatic fate determinant in melanoma.”. Journal of Experimental & Clinical Cancer Research 38 (1): 17. doi:10.1186/s13046-018-0998-6. PMC 6330758. PMID 30642390. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330758/. 
  17. ^ “Changes in Fluorescence Recovery After Photobleaching (FRAP) as an indicator of SOX9 transcription factor activity”. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1862 (1): 107–117. (January 2019). doi:10.1016/j.bbagrm.2018.11.001. PMID 30465885. 
  18. ^ “SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite”. American Journal of Medical Genetics 90 (1): 25–8. (January 2000). doi:10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5. PMID 10602113. 
  19. ^ “SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex”. Nucleic Acids Research 30 (14): 3245–52. (July 2002). doi:10.1093/nar/gkf443. PMC 135763. PMID 12136106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC135763/6 
  20. ^ “A new long form of c-Maf cooperates with Sox9 to activate the type II collagen gene”. The Journal of Biological Chemistry 277 (52): 50668–75. (December 2002). doi:10.1074/jbc.M206544200. PMID 12381733. 
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