SOX2

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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 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. Sox2 has a critical role in maintenance of embryonic and neural stem cells and holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine. [1]

Mutations in this gene have been linked with bilateral anophthalmia, a severe structural eye deformity. [2]

Function and Expression in 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] Despite the importance of SOX2 in regulating OCT4, in the earliest days of the morula in mice, knocking out SOX2 does not affect OCT4 expression. However, downregulation of SOX2 at the two cell stage results in a knockdown of CDX2 and FGF4, and leads to an increase in cell apoptosis and an increased inability to form the trophectoderm. This led researchers to a few insights, primarily that early trophectoderm differentiation and lineage progression is promoted and controlled partially by SOX2 [7]. This raises some questions about the interaction of SOX2 and CDX2 in regards to the initial segregation of the ICM and trophectoderm.

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. [11]

Role in Reprogramming

In a ground breaking experiment involving induced pluripotent stem cells, it was discovered that Sox2 in conjunction with Oct4, c-Myc and Klf4 were sufficient for inducing pluripotency in mouse embryonic stem cells. [12] In another similar experiment involving human fibroblasts, the Thomson reprogramming factors of Oct-4, Sox2, Nanog, and Lin28 also were found to be sufficient for reprogramming, with Sox2 being necessary for this process.[13] The discovery that expression of only four transcription factors was necessary to induce pluripotency was pivotal for the future of regenerative medicine.

Role in Neural Stem Cells

In neurogenesis, Sox2 is expressed throughout developing cells in the neural tube as well as in proliferating CNS progenitors. However, Sox2 is downregulated during progenitors' final cell cycle during differentiation when they become post mitotic. [14] Cells expressing Sox2 are capable of both producing cells identical to themselves and differentiated neural cell types, two necessary hallmarks of stem cells. Proliferation of Sox2+ neural stem cells can generate neural precursors as well as Sox2+ neural stem cell population. [15]

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. [16]

Interactions

SOX2 has been shown to interact with PAX6,[17] NPM1 [18] and Oct4. [5] SOX2 has been found to cooperatively regulate Rex1 with Oct3/4.[19]

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. [20] 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. [21]

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. Sox2 is a key upregulated factor in lung squamous cell carcinoma, directing many genes involved in tumor progression. Its overexpression also activates cellular migration and anchorage-independent growth. [22]

The ectopic expression of SOX2 may be related to abnormal differentiation of colorectal cancer cells.[23]

References

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Further reading

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External links

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