SOX2

Last updated

SOX2
Protein SOX2 PDB 1gt0.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SOX2 , ANOP3, MCOPS3, SRY-box 2, Sox2, SRY-box transcription factor 2
External IDs OMIM: 184429 MGI: 98364 HomoloGene: 68298 GeneCards: SOX2
Orthologs
SpeciesHumanMouse
Entrez

6657

20674

Ensembl

ENSG00000181449

ENSMUSG00000074637

UniProt

P48431

P48432

RefSeq (mRNA)

NM_003106

NM_011443

RefSeq (protein)

NP_003097

NP_035573

Location (UCSC) Chr 3: 181.71 – 181.71 Mb Chr 3: 34.7 – 34.71 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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. [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]

Sox2 expression is also found in high gleason grade prostate cancer, and promotes castration-resistant prostate cancer growth. [28]

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]

Interactions

SOX2 has been shown to interact with PAX6, [35] NPM1, [7] and Oct4. [9] SOX2 has been found to cooperatively regulate Rex1 with Oct3/4. [36]

Related Research Articles

<span class="mw-page-title-main">Cellular differentiation</span> Developmental biology

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. However, metabolic composition does get altered quite dramatically where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.

<span class="mw-page-title-main">Oct-4</span> Mammalian protein found in Homo sapiens

Oct-4, also known as POU5F1, is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.

<span class="mw-page-title-main">Homeobox protein NANOG</span> Mammalian protein found in humans

Homeobox protein NANOG(hNanog) is a transcriptional factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors. hNanog is encoded in humans by the NANOG gene. Several types of cancer are associated with NANOG.

In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.

SOX genes encode a family of transcription factors that bind to the minor groove in DNA, and belong to a super-family of genes characterized by a homologous sequence called the HMG-box. This HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species. Homologues have been identified in insects, nematodes, amphibians, reptiles, birds and a range of mammals. However, HMG boxes can be very diverse in nature, with only a few amino acids being conserved between species.

<span class="mw-page-title-main">Inner cell mass</span> Early embryonic mass that gives rise to the fetus

The inner cell mass (ICM) or embryoblast is a structure in the early development of an embryo. It is the mass of cells inside the blastocyst that will eventually give rise to the definitive structures of the fetus. The inner cell mass forms in the earliest stages of embryonic development, before implantation into the endometrium of the uterus. The ICM is entirely surrounded by the single layer of trophoblast cells of the trophectoderm.

<span class="mw-page-title-main">Induced pluripotent stem cell</span> Pluripotent stem cell generated directly from a somatic cell

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

<span class="mw-page-title-main">FOXP1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.

<span class="mw-page-title-main">TBX3</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX3 is a protein that in humans is encoded by the TBX3 gene.

<span class="mw-page-title-main">SALL4</span> Protein-coding gene in the species Homo sapiens

Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.

<span class="mw-page-title-main">Rex1</span> Known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells

Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begin to differentiate, Rex1 is severely and abruptly downregulated.

<span class="mw-page-title-main">FOXD3</span> Protein-coding gene in the species Homo sapiens

Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the FOXD3 gene.

<span class="mw-page-title-main">SOX1</span> Transcription factor gene of the SOX family

SOX1 is a gene that encodes a transcription factor with a HMG-box DNA-binding domain and functions primarily in neurogenesis. SOX1, SOX2 and SOX3, members of the SOX gene family, contain transcription factors related to SRY, the testis-determining factor.

A mesenchymal–epithelial transition (MET) is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial–mesenchymal transition (EMT) and it has been shown to occur in normal development, induced pluripotent stem cell reprogramming, cancer metastasis and wound healing.

<span class="mw-page-title-main">Cell potency</span> Ability of a cell to differentiate into other cell types

Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.

Embryonic stem cells are capable of self-renewing and differentiating to the desired fate depending on their position in the body. Stem cell homeostasis is maintained through epigenetic mechanisms that are highly dynamic in regulating the chromatin structure as well as specific gene transcription programs. Epigenetics has been used to refer to changes in gene expression, which are heritable through modifications not affecting the DNA sequence.

Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor or unipotent – (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

<span class="mw-page-title-main">SOX17</span> Protein-coding gene in the species Homo sapiens

SRY-box 17 is a protein that in humans is encoded by the SOX17 gene.

<span class="mw-page-title-main">F-box protein 15</span>

F-box protein 15 also known as Fbx15 is a protein that in humans is encoded by the FBXO15 gene.

<span class="mw-page-title-main">David Suter (biologist)</span> David Suter, Swiss cell biologist

David Suter is a Swiss physician and molecular and cell biologist. His research focuses on quantitative approaches to study gene expression and developmental cell fate decisions. He is currently a professor at EPFL, where he heads the Suter Lab at the Institute of Bioengineering of the School of Life Sciences.

References

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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ↑ Rizzino A (2009). "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. doi:10.1002/wsbm.12. PMC   2794141 . PMID   20016762.
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  27. ↑ Hussenet T, Dali S, Exinger J, Monga B, Jost B, Dembelé D, et al. (January 2010). "SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas". PLOS ONE. 5 (1): e8960. Bibcode:2010PLoSO...5.8960H. doi: 10.1371/journal.pone.0008960 . PMC   2813300 . PMID   20126410.
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  31. ↑ Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K (November 2009). "Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors". Cell Stem Cell. 5 (5): 504–514. doi: 10.1016/j.stem.2009.08.018 . PMID   19896441.
  32. ↑ Gangemi RM, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, et al. (January 2009). "SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity". Stem Cells. 27 (1): 40–48. doi: 10.1634/stemcells.2008-0493 . PMID   18948646. S2CID   19125999.
  33. 1 2 López-Juárez A, Remaud S, Hassani Z, Jolivet P, Pierre Simons J, Sontag T, et al. (May 2012). "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. doi: 10.1016/j.stem.2012.04.008 . PMID   22560077.
  34. ↑ Wisse B. Hypothyroidism: MedlinePlus Medical Encyclopedia. U.S National Library of Medicine. Retrieved 10 April 2014.
  35. ↑ 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. doi:10.1016/S0012-1606(03)00058-7. PMID   12710953.
  36. ↑ Shi W, Wang H, Pan G, Geng Y, Guo Y, Pei D (August 2006). "Regulation of the pluripotency marker Rex-1 by Nanog and Sox2". The Journal of Biological Chemistry. 281 (33): 23319–23325. doi: 10.1074/jbc.M601811200 . PMID   16714766.

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