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.[5]
Sox2 holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine.[6]
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.[7]
NPM1, a transcriptional regulator involved in cell proliferation, individually forms
complexes with Sox2,
Oct4 and
Nanog in embryonic stem cells.[8] 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.[9] 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.[10]
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.[11] 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[12] and post-transcriptional suppression of Sox2 by miR134.[13]
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.[14]Npm1/Sox2 complexes are sustained when differentiation is induced along the ectodermal lineage, emphasizing an important functional role for Sox2 in ectodermal differentiation.[8] 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.[15]
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.[16]
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.[17] 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.[18] Proliferation of Sox2+
neural stem cells can generate neural precursors as well as Sox2+ neural stem cell population.[19] 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.[20]
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.[21]
Eye deformities
Mutations in this gene have been linked with bilateral
anophthalmia, a severe structural eye deformity.[22]
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.[23] 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.[24]
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. [25] 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.[26] Its overexpression also activates cellular migration and anchorage-independent growth.[27]
The ectopic expression of SOX2 may be related to abnormal differentiation of
colorectal cancer cells.[29]
Sox2 has been shown to be relevant in the development of Tamoxifen resistance in breast cancer.[30]
In
Glioblastoma multiforme, Sox2 is a well-established stem cell transcription factor needed to induce and maintain stemness properties of glioblastoma cancer cells.[31][32]
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.[33]
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.[33]
Hypothyroidism can arise from a multitude of causes, and is commonly remedied with hormone treatments such as the commonly used
Levothyroxine.[34]
^Ferri AL, Cavallaro M, Braida D, Di Cristofano A, Canta A, Vezzani A, et al. (August 2004). "Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain". Development. 131 (15): 3805–3819.
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^van Olphen SH, Biermann K, Shapiro J, Wijnhoven BP, Toxopeus EL, van der Gaast A, et al. (February 2017). "P53 and SOX2 Protein Expression Predicts Esophageal Adenocarcinoma in Response to Neoadjuvant Chemoradiotherapy". Annals of Surgery. 265 (2): 347–355.
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^Tani Y, Akiyama Y, Fukamachi H, Yanagihara K, Yuasa Y (April 2007). "Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression". Journal of Cancer Research and Clinical Oncology. 133 (4): 263–269.
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^Aota S, Nakajima N, Sakamoto R, Watanabe S, Ibaraki N, Okazaki K (May 2003). "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.
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Kamachi Y, Uchikawa M, Kondoh H (April 2000). "Pairing SOX off: with partners in the regulation of embryonic development". Trends in Genetics. 16 (4): 182–187.
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Stevanovic M, Zuffardi O, Collignon J, Lovell-Badge R, Goodfellow P (October 1994). "The cDNA sequence and chromosomal location of the human SOX2 gene". Mammalian Genome. 5 (10): 640–642.
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Aota S, Nakajima N, Sakamoto R, Watanabe S, Ibaraki N, Okazaki K (May 2003). "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.
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Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, et al. (March 2004). "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. 130 (3): 135–145.
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1gt0: CRYSTAL STRUCTURE OF A POU/HMG/DNA TERNARY COMPLEX
1o4x: TERNARY COMPLEX OF THE DNA BINDING DOMAINS OF THE OCT1 AND SOX2 TRANSCRIPTION FACTORS WITH A 19MER OLIGONUCLEOTIDE FROM THE HOXB1 REGULATORY ELEMENT