Biology:SOX2

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Short description: Transcription factor gene of the SOX family


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.[1]

Sox2 is a member of the Sox family of transcription factors, which have been shown to play key roles in many stages of mammalian development. This protein family shares highly conserved DNA binding domains known as HMG (High-mobility group) box domains containing approximately 80 amino acids.[1]

Sox2 holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine.[2]

Function

Stem cell pluripotency

LIF (Leukemia inhibitory factor) signaling, which maintains pluripotency in mouse embryonic stem cells, activates Sox2 downstream of the JAK-STAT signaling pathway and subsequent activation of Klf4 (a member of the family of Kruppel-like factors). Oct-4, Sox2 and Nanog positively regulate transcription of all pluripotency circuitry proteins in the LIF pathway.[3]

NPM1, a transcriptional regulator involved in cell proliferation, individually forms complexes with Sox2, Oct4 and Nanog in embryonic stem cells.[4] These three pluripotency factors contribute to a complex molecular network that regulates a number of genes controlling pluripotency. Sox2 binds to DNA cooperatively with Oct4 at non-palindromic sequences to activate transcription of key pluripotency factors.[5] Surprisingly, regulation of Oct4-Sox2 enhancers can occur without Sox2, likely due to expression of other Sox proteins. However, a group of researchers concluded that the primary role of Sox2 in embryonic stem cells is controlling Oct4 expression, and they both perpetuate their own expression when expressed concurrently.[6]

In an experiment involving mouse embryonic stem cells, it was discovered that Sox2 in conjunction with Oct4, c-Myc and Klf4 were sufficient for producing induced pluripotent stem cells.[7] The discovery that expression of only four transcription factors was necessary to induce pluripotency allowed future regenerative medicine research to be conducted considering minor manipulations.

Loss of pluripotency is regulated by hypermethylation of some Sox2 and Oct4 binding sites in male germ cells[8] and post-transcriptional suppression of Sox2 by miR134.[9]

Varying levels of Sox2 affect embryonic stem cells' fate of differentiation. Sox2 inhibits differentiation into the mesendoderm germ layer and promotes differentiation into neural ectoderm germ layer.[10] Npm1/Sox2 complexes are sustained when differentiation is induced along the ectodermal lineage, emphasizing an important functional role for Sox2 in ectodermal differentiation.[4] The loss of Sox2 has also been shown to affect naïve pluripotency, with Sox2-depleted mouse embryonic cells becoming able to differentiate into extraembryonic trophoblast.[11]

Deficiency of Sox2 in mice has been shown to result in neural malformities and eventually fetal death, further underlining Sox2's vital role in embryonic development.[12]

Neural stem cells

In neurogenesis, Sox2 is expressed throughout developing cells in the neural tube as well as in proliferating central nervous system progenitors. However, Sox2 is downregulated during progenitors' final cell cycle during differentiation when they become post mitotic.[13] Cells expressing Sox2 are capable of both producing cells identical to themselves and differentiated neural cell types, two necessary hallmarks of stem cells. Thus signals controlling Sox2 expression in the presumptive neuronal compartment, like Notch signaling, control what size the neuronal compartment finally reaches.[14] Proliferation of Sox2+ neural stem cells can generate neural precursors as well as Sox2+ neural stem cell population.[15] Differences in brain size between the species thus relate to the capacity of different species to maintain SOX2 expression in the developing neural systems. The difference in brain size between humans and apes, for instance, has been linked to mutations in the gene Asb11, which is an upstream activator of SOX2 in the developing neural system.[16]

Induced pluripotency is possible using adult neural stem cells, which express higher levels of Sox2 and c-Myc than embryonic stem cells. Therefore, only two exogenous factors, one of which is necessarily Oct4, are sufficient for inducing pluripotent cells from neural stem cells, lessening the complications and risks associated with introducing multiple factors to induce pluripotency.[17]

Eye deformities

Mutations in this gene have been linked with bilateral anophthalmia, a severe structural eye deformity.[18]

Cancer

In lung development, Sox2 controls the branching morphogenesis of the bronchial tree and differentiation of the epithelium of airways. Overexpression causes an increase in neuroendocrine, gastric/intestinal and basal cells.[19] Under normal conditions, Sox2 is critical for maintaining self-renewal and appropriate proportion of basal cells in adult tracheal epithelium. However, its overexpression gives rise to extensive epithelial hyperplasia and eventually carcinoma in both developing and adult mouse lungs.[20]

In squamous cell carcinoma, gene amplifications frequently target the 3q26.3 region. The gene for Sox2 lies within this region, which effectively characterizes Sox2 as an oncogene, although in adenocarcinoma of the esophagus loss of Sox2 is strongly associated with worse prognosis, effectively characterising Sox2 as a tumor suppressor. It thus fair to say that the function of SOX2 in cancer is pleiotropic. [21] Sox2 is a key upregulated factor in lung squamous cell carcinoma, directing many genes involved in tumor progression. Sox2 overexpression cooperates with loss of Lkb1 expression to promote squamous cell lung cancer in mice.[22] Its overexpression also activates cellular migration and anchorage-independent growth.[23]

Sox2 expression is also found in high gleason grade prostate cancer, and promotes castration-resistant prostate cancer growth.[24]

The ectopic expression of SOX2 may be related to abnormal differentiation of colorectal cancer cells.[25]

Sox2 has been shown to be relevant in the development of Tamoxifen resistance in breast cancer.[26]

In Glioblastoma multiforme, Sox2 is a well-established stem cell transcription factor needed to induce and maintain stemness properties of glioblastoma cancer cells.[27][28]

Regulation by thyroid hormone

There are three thyroid hormone response elements (TREs) in the region upstream of the Sox2 promoter. This region is known as the enhancer region. Studies have suggested that thyroid hormone (T3) controls Sox2 expression via the enhancer region. The expression of TRα1 (thyroid hormone receptor) is increased in proliferating and migrating neural stem cells. It has therefore been suggested that transcriptional repression of Sox2, mediated by the thyroid hormone signaling axis, allows for neural stem cell commitment and migration from the sub-ventricular zone. A deficiency of thyroid hormone, particularly during the first trimester, will lead to abnormal central nervous system development.[29] Further supporting this conclusion is the fact that hypothyroidism during fetal development can result in a variety of neurological deficiencies, including cretinism, characterized by stunted physical development and mental retardation.[29]

Hypothyroidism can arise from a multitude of causes, and is commonly remedied with hormone treatments such as the commonly used Levothyroxine.[30]

Interactions

SOX2 has been shown to interact with PAX6,[31] NPM1,[3] and Oct4.[5] SOX2 has been found to cooperatively regulate Rex1 with Oct3/4.[32]

References

  1. ↑ 1.0 1.1 "SOX2". NCBI. https://www.ncbi.nlm.nih.gov/gene/6657. 
  2. ↑ "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 1 (2): 228–236. 2009. doi:10.1002/wsbm.12. PMID 20016762. 
  3. ↑ 3.0 3.1 "A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells". Nature 460 (7251): 118–122. July 2009. doi:10.1038/nature08113. PMID 19571885. Bibcode: 2009Natur.460..118N. 
  4. ↑ 4.0 4.1 "Core transcription factors, Oct4, Sox2 and Nanog, individually form complexes with nucleophosmin (Npm1) to control embryonic stem (ES) cell fate determination". Aging 2 (11): 815–822. November 2010. doi:10.18632/aging.100222. PMID 21076177. 
  5. ↑ 5.0 5.1 "The transcriptional foundation of pluripotency". Development 136 (14): 2311–2322. July 2009. doi:10.1242/dev.024398. PMID 19542351. 
  6. ↑ "Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells". Nature Cell Biology 9 (6): 625–635. June 2007. doi:10.1038/ncb1589. PMID 17515932. 
  7. ↑ "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell 126 (4): 663–676. August 2006. doi:10.1016/j.cell.2006.07.024. PMID 16904174. 
  8. ↑ "Transcriptional repression and DNA hypermethylation of a small set of ES cell marker genes in male germline stem cells". BMC Developmental Biology 6: 34. July 2006. doi:10.1186/1471-213X-6-34. PMID 16859545. 
  9. ↑ "MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation". Nature 455 (7216): 1124–1128. October 2008. doi:10.1038/nature07299. PMID 18806776. Bibcode: 2008Natur.455.1124T. 
  10. ↑ "Pluripotency factors in embryonic stem cells regulate differentiation into germ layers". Cell 145 (6): 875–889. June 2011. doi:10.1016/j.cell.2011.05.017. PMID 21663792. 
  11. ↑ "Sox2 modulation increases naïve pluripotency plasticity" (in English). iScience 24 (3): 102153. March 2021. doi:10.1016/j.isci.2021.102153. PMID 33665571. Bibcode: 2021iSci...24j2153T. 
  12. ↑ "Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain". Development 131 (15): 3805–3819. August 2004. doi:10.1242/dev.01204. PMID 15240551. 
  13. ↑ "SOX2 functions to maintain neural progenitor identity". Neuron 39 (5): 749–765. August 2003. doi:10.1016/S0896-6273(03)00497-5. PMID 12948443. 
  14. ↑ "Signaling Size: Ankyrin and SOCS Box-Containing ASB E3 Ligases in Action". Trends in Biochemical Sciences 44 (1): 64–74. January 2019. doi:10.1016/j.tibs.2018.10.003. PMID 30446376. 
  15. ↑ "In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus". Cell Stem Cell 1 (5): 515–528. November 2007. doi:10.1016/j.stem.2007.09.002. PMID 18371391. 
  16. ↑ "The novel gene asb11: a regulator of the size of the neural progenitor compartment". The Journal of Cell Biology 174 (4): 581–592. August 2006. doi:10.1083/jcb.200601081. PMID 16893969. 
  17. ↑ "Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors". Nature 454 (7204): 646–650. July 2008. doi:10.1038/nature07061. PMID 18594515. Bibcode: 2008Natur.454..646K. 
  18. ↑ "Entrez Gene: SOX2 SRY (sex determining region Y)-box 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6657. 
  19. ↑ "Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation". Developmental Biology 317 (1): 296–309. May 2008. doi:10.1016/j.ydbio.2008.02.035. PMID 18374910. 
  20. ↑ "Evidence that SOX2 overexpression is oncogenic in the lung". PLOS ONE 5 (6): e11022. June 2010. doi:10.1371/journal.pone.0011022. PMID 20548776. Bibcode: 2010PLoSO...511022L. 
  21. ↑ "P53 and SOX2 Protein Expression Predicts Esophageal Adenocarcinoma in Response to Neoadjuvant Chemoradiotherapy". Annals of Surgery 265 (2): 347–355. February 2017. doi:10.1097/SLA.0000000000001625. PMID 28059963. 
  22. ↑ "Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer". Cell Reports 8 (1): 40–49. July 2014. doi:10.1016/j.celrep.2014.05.036. PMID 24953650. 
  23. ↑ "SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas". PLOS ONE 5 (1): e8960. January 2010. doi:10.1371/journal.pone.0008960. PMID 20126410. Bibcode: 2010PLoSO...5.8960H. 
  24. ↑ "Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer". PLOS ONE 8 (1): e53701. 2013. doi:10.1371/journal.pone.0053701. PMID 23326489. Bibcode: 2013PLoSO...853701K. 
  25. ↑ "Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression". Journal of Cancer Research and Clinical Oncology 133 (4): 263–269. April 2007. doi:10.1007/s00432-006-0165-x. PMID 17136346. 
  26. ↑ "Sox2 promotes tamoxifen resistance in breast cancer cells". EMBO Molecular Medicine 6 (1): 66–79. January 2014. doi:10.1002/emmm.201303411. PMID 24178749. 
  27. ↑ "Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors". Cell Stem Cell 5 (5): 504–514. November 2009. doi:10.1016/j.stem.2009.08.018. PMID 19896441. 
  28. ↑ "SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity". Stem Cells 27 (1): 40–48. January 2009. doi:10.1634/stemcells.2008-0493. PMID 18948646. 
  29. ↑ 29.0 29.1 "Thyroid hormone signaling acts as a neurogenic switch by repressing Sox2 in the adult neural stem cell niche". Cell Stem Cell 10 (5): 531–543. May 2012. doi:10.1016/j.stem.2012.04.008. PMID 22560077. 
  30. ↑ Wisse B. "Hypothyroidism: MedlinePlus Medical Encyclopedia.". Hypothyroidism: MedlinePlus Medical Encyclopedia.. U.S National Library of Medicine. https://www.nlm.nih.gov/medlineplus/ency/article/000353.htm. Retrieved 10 April 2014. 
  31. ↑ "Pax6 autoregulation mediated by direct interaction of Pax6 protein with the head surface ectoderm-specific enhancer of the mouse Pax6 gene". Developmental Biology 257 (1): 1–13. May 2003. doi:10.1016/S0012-1606(03)00058-7. PMID 12710953. 
  32. ↑ "Regulation of the pluripotency marker Rex-1 by Nanog and Sox2". The Journal of Biological Chemistry 281 (33): 23319–23325. August 2006. doi:10.1074/jbc.M601811200. PMID 16714766. 

Further reading

External links



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