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1
Li, Pu-Yu, Ping Wang, She-Gan Gao, and Dao-Yin Dong. "Long Noncoding RNA SOX2-OT: Regulations, Functions, and Roles on Mental Illnesses, Cancers, and Diabetic Complications." BioMed Research International 2020 (November 26, 2020): 1–12. http://dx.doi.org/10.1155/2020/2901589.
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SRY-box transcription factor 2 (SOX2) overlapping transcript (SOX2-OT) is an evolutionarily conserved long noncoding RNA. Its intronic region contains the SOX2 gene, the major regulator of the pluripotency of embryonic stem cells. The human SOX2-OT gene comprises multiple exons and has multiple transcription start sites and generates hundreds of transcripts. Transcription factors (IRF4, AR, and SOX3), transcriptional inhibitors (NSPc1, MTA3, and YY1), and miRNAs (miR-211 and miR-375) have been demonstrated to control certain SOX2-OT transcript level at the transcriptional or posttranscriptional levels. Accumulated evidence indicates its crucial roles in the regulation of the SOX2 gene, miRNAs, and transcriptional process. Restricted expression of SOX2-OT transcripts in the brain results in the association between SOX2-OT single nucleotide polymorphisms and mental illnesses such as schizophrenia and anorexia nervosa. SOX2-OT is notably elevated in tumor tissues, and a high level of SOX2-OT is well correlated with poor clinical outcomes in cancer patients, leading to the establishment of its role as an oncogene and a prognostic or diagnostic biomarker for cancers. The emerging evidence supports that SOX2-OT mediates diabetic complications. In summary, SOX2-OT has diversified functions and could be a therapeutic target for various diseases.
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Milivojevic, Milena, Gordana Nikcevic, Natasa Kovacevic-Grujicic, A. Krstic, Marija Mojsin, Danijela Drakulic, and Milena Stevanovic. "Involvement of ubiquitous and tale transcription factors, as well as liganded RXRα, in the regulation of human SOX2 gene expression in the NT2/D1 embryonal carcinoma cell line." Archives of Biological Sciences 62, no. 2 (2010): 199–210. http://dx.doi.org/10.2298/abs1002199m.
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SOX2 is a key transcription factor in embryonic development representing a universal marker of pluripotent stem cells. Based on the functional redundancy and overlapping expression patterns of SOXB1 subgroup members during development, the goal of this study has been to analyze if some aspects of regulation of expression are preserved between human SOX2 and SOX3 genes. Thus, we have tested several transcription factors previously demonstrated to play roles in controlling SOX3 gene activity for potential participation in the regulation of SOX2 gene expression in NT2/D1 cells. Here we report on the activation of SOX2 expression by ubiquitous transcription factors (NF-Y, Sp1 and MAZ), TALE family members (Pbx1 and Meis1), as well as liganded RXR?. Elucidating components involved in the regulation of SOX gene expression represent a valuable contribution in unraveling the regulatory networks operating in pluripotent embryonic cells.
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Tan, Cheng, and Shoji Takada. "Nucleosome allostery in pioneer transcription factor binding." Proceedings of the National Academy of Sciences 117, no. 34 (August 10, 2020): 20586–96. http://dx.doi.org/10.1073/pnas.2005500117.
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While recent experiments revealed that some pioneer transcription factors (TFs) can bind to their target DNA sequences inside a nucleosome, the binding dynamics of their target recognitions are poorly understood. Here we used the latest coarse-grained models and molecular dynamics simulations to study the nucleosome-binding procedure of the two pioneer TFs, Sox2 and Oct4. In the simulations for a strongly positioning nucleosome, Sox2 selected its target DNA sequence only when the target was exposed. Otherwise, Sox2 entropically bound to the dyad region nonspecifically. In contrast, Oct4 plastically bound on the nucleosome mainly in two ways. First, the two POU domains of Oct4 separately bound to the two parallel gyres of the nucleosomal DNA, supporting the previous experimental results of the partial motif recognition. Second, the POUSdomain of Oct4 favored binding on the acidic patch of histones. Then, simulating the TFs binding to a genomic nucleosome, theLIN28Bnucleosome, we found that the recognition of a pseudo motif by Sox2 induced the local DNA bending and shifted the population of the rotational position of the nucleosomal DNA. The redistributed DNA phase, in turn, changed the accessibility of a distant TF binding site, which consequently affected the binding probability of a second Sox2 or Oct4. These results revealed a nucleosomal DNA-mediated allosteric mechanism, through which one TF binding event can change the global conformation, and effectively regulate the binding of another TF at distant sites. Our simulations provide insights into the binding mechanism of single and multiple TFs on the nucleosome.
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Moosa, Mahdi, Phoebe Tsoi, Kyoung-Jae Choi, Allan Ferreon, and Josephine Ferreon. "Direct Single-Molecule Observation of Sequential DNA Bending Transitions by the Sox2 HMG Box." International Journal of Molecular Sciences 19, no. 12 (December 4, 2018): 3865. http://dx.doi.org/10.3390/ijms19123865.
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Sox2 is a pioneer transcription factor that initiates cell fate reprogramming through locus-specific differential regulation. Mechanistically, it was assumed that Sox2 achieves its regulatory diversity via heterodimerization with partner transcription factors. Here, utilizing single-molecule fluorescence spectroscopy, we show that Sox2 alone can modulate DNA structural landscape in a dosage-dependent manner. We propose that such stoichiometric tuning of regulatory DNAs is crucial to the diverse biological functions of Sox2, and represents a generic mechanism of conferring functional plasticity and multiplicity to transcription factors.
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Gandhi, Neha S., Edina Wang, Anabel Sorolla, Yu Jie Kan, Adil Malik, Jyotsna Batra, Kimberly A. Young, Wan Jun Tie, Pilar Blancafort, and Ricardo L. Mancera. "Design and Characterization of a Cell-Penetrating Peptide Derived from the SOX2 Transcription Factor." International Journal of Molecular Sciences 22, no. 17 (August 28, 2021): 9354. http://dx.doi.org/10.3390/ijms22179354.
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SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival in patients affected with breast cancer. Given its key role as a master regulator of cell proliferation, SOX2 represents an important scaffold for the engineering of dominant-negative synthetic DNA-binding domains (DBDs) that act by blocking or interfering with the oncogenic activity of the endogenous transcription factor in cancer cells. We have synthesized an interference peptide (iPep) encompassing a truncated 24 amino acid long C-terminus of SOX2 containing a potential SOX-specific nuclear localization sequence, and the determinants of the binding of SOX2 to the DNA and to its transcription factor binding partners. We found that the resulting peptide (SOX2-iPep) possessed intrinsic cell penetration and promising nuclear localization into breast cancer cells, and decreased cellular proliferation of SOX2 overexpressing cell lines. The novel SOX2-iPep was found to exhibit a random coil conformation predominantly in solution. Molecular dynamics simulations were used to characterize the interactions of both the SOX2 transcription factor and the SOX2-iPep with FGF4-enhancer DNA in the presence of the POU domain of the partner transcription factor OCT4. Predictions of the free energy of binding revealed that the iPep largely retained the binding affinity for DNA of parental SOX2. This work will enable the future engineering of novel dominant interference peptides to transport different therapeutic cargo molecules such as anti-cancer drugs into cells.
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Dash, Soma, Lindy K. Brastrom, Shaili D. Patel, C. Anthony Scott, Diane C. Slusarski, and Salil A. Lachke. "The master transcription factor SOX2, mutated in anophthalmia/microphthalmia, is post-transcriptionally regulated by the conserved RNA-binding protein RBM24 in vertebrate eye development." Human Molecular Genetics 29, no. 4 (December 9, 2019): 591–604. http://dx.doi.org/10.1093/hmg/ddz278.
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Abstract Mutations in the key transcription factor, SOX2, alone account for 20% of anophthalmia (no eye) and microphthalmia (small eye) birth defects in humans—yet its regulation is not well understood, especially on the post-transcription level. We report the unprecedented finding that the conserved RNA-binding motif protein, RBM24, positively controls Sox2 mRNA stability and is necessary for optimal SOX2 mRNA and protein levels in development, perturbation of which causes ocular defects, including microphthalmia and anophthalmia. RNA immunoprecipitation assay indicates that RBM24 protein interacts with Sox2 mRNA in mouse embryonic eye tissue. and electrophoretic mobility shift assay shows that RBM24 directly binds to the Sox2 mRNA 3’UTR, which is dependent on AU-rich elements (ARE) present in the Sox2 mRNA 3’UTR. Further, we demonstrate that Sox2 3’UTR AREs are necessary for RBM24-based elevation of Sox2 mRNA half-life. We find that this novel RBM24–Sox2 regulatory module is essential for early eye development in vertebrates. We show that Rbm24-targeted deletion using a constitutive CMV-driven Cre in mouse, and rbm24a-CRISPR/Cas9-targeted mutation or morpholino knockdown in zebrafish, results in Sox2 downregulation and causes the developmental defects anophthalmia or microphthalmia, similar to human SOX2-deficiency defects. We further show that Rbm24 deficiency leads to apoptotic defects in mouse ocular tissue and downregulation of eye development markers Lhx2, Pax6, Jag1, E-cadherin and gamma-crystallins. These data highlight the exquisite specificity that conserved RNA-binding proteins like RBM24 mediate in the post-transcriptional control of key transcription factors, namely, SOX2, associated with organogenesis and human developmental defects.
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Yamatsuji, Tomoki, Etsuko Yokota, Takashi Sera, Noriaki Manabe, Takuya Fukazawa, and Yoshio Naomoto. "PS02.047: TARGETED SILENCING OF SOX2 BY AN ARTIFICIAL TRANSCRIPTION FACTOR SUPPRESSED THE GROWTH OF ESOPHAGEAL CANCER CELLS." Diseases of the Esophagus 31, Supplement_1 (September 1, 2018): 133–34. http://dx.doi.org/10.1093/dote/doy089.ps02.047.
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Abstract Background SOX2 is a transcription factor that is fundamental for early development and for the maintenance of stem cells in multiple adult tissues and also plays an important role in squamous cell differentiation. Amplification of chromosome 3q26 is the most common of the genetic alterations found in squamous cell carcinoma (SCC). SOX2 is a candidate oncogene present in this locus and amplification of SOX2 has been reported in lung and esophageal squamous cell SCC. In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. Methods We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in esophageal SCC cells(TE1 and TE4) expressing SOX2. Results Ad-ATF/SOX2 decreased esophageal SCC cells proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a SCC xenograft mouse model. Conclusion In this study, we have shown that the targeted down-regulation of SOX2 using ATF based technologies can be used as an effective tool for the treatment of SCC in esophageal cancers that express SOX2. Our results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for esophageal SCC. Disclosure All authors have declared no conflicts of interest.
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Aguilar-Medina, Maribel, Mariana Avendaño-Félix, Erik Lizárraga-Verdugo, Mercedes Bermúdez, José Geovanni Romero-Quintana, Rosalío Ramos-Payan, Erika Ruíz-García, and César López-Camarillo. "SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer." Journal of Oncology 2019 (April 1, 2019): 1–16. http://dx.doi.org/10.1155/2019/6754040.
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Transcriptional and epigenetic embryonic programs can be reactivated in cancer cells. As result, a specific subset of undifferentiated cells with stem-cells properties emerges and drives tumorigenesis. Recent findings have shown that ectoderm- and endoderm-derived tissues continue expressing stem-cells related transcription factors of the SOX-family of proteins such as SOX2 and SOX9 which have been implicated in the presence of cancer stem-like cells (CSCs) in tumors. Currently, there is enough evidence suggesting an oncogenic role for SOX9 in different types of human cancers. This review provides a summary of the current knowledge about the involvement of SOX9 in development and progression of cancer. Understanding the functional roles of SOX9 and clinical relevance is crucial for developing novel treatments targeting CSCs in cancer.
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POLAKOVA, INGRID, MARTINA DUSKOVA, and MICHAL SMAHEL. "Antitumor DNA vaccination against the Sox2 transcription factor." International Journal of Oncology 45, no. 1 (April 28, 2014): 139–46. http://dx.doi.org/10.3892/ijo.2014.2402.
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Lu, Yurong, Yiwen Zhu, Shihan Deng, Yuhuang Chen, Wei Li, Jing Sun, and Xiulong Xu. "Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)—Related Transcription Factors and CSC-Driven Thyroid Tumor Growth." Cancers 13, no. 3 (January 22, 2021): 418. http://dx.doi.org/10.3390/cancers13030418.
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The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence.
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Cheng, Arthur H., Samuel W. Fung, Sara Hegazi, Osama Hasan Mustafa Hasan Abdalla, and Hai-Ying Mary Cheng. "SOX2 Regulates Neuronal Differentiation of the Suprachiasmatic Nucleus." International Journal of Molecular Sciences 23, no. 1 (December 26, 2021): 229. http://dx.doi.org/10.3390/ijms23010229.
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In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.
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Mercurio, Sara, Linda Serra, and Silvia K. Nicolis. "More than just Stem Cells: Functional Roles of the Transcription Factor Sox2 in Differentiated Glia and Neurons." International Journal of Molecular Sciences 20, no. 18 (September 13, 2019): 4540. http://dx.doi.org/10.3390/ijms20184540.
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The Sox2 transcription factor, encoded by a gene conserved in animal evolution, has become widely known because of its functional relevance for stem cells. In the developing nervous system, Sox2 is active in neural stem cells, and important for their self-renewal; differentiation to neurons and glia normally involves Sox2 downregulation. Recent evidence, however, identified specific types of fully differentiated neurons and glia that retain high Sox2 expression, and critically require Sox2 function, as revealed by functional studies in mouse and in other animals. Sox2 was found to control fundamental aspects of the biology of these cells, such as the development of correct neuronal connectivity. Sox2 downstream target genes identified within these cell types provide molecular mechanisms for cell-type-specific Sox2 neuronal and glial functions. SOX2 mutations in humans lead to a spectrum of nervous system defects, involving vision, movement control, and cognition; the identification of neurons and glia requiring Sox2 function, and the investigation of Sox2 roles and molecular targets within them, represents a novel perspective for the understanding of the pathogenesis of these defects.
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Hou, Linlin, Yuanjie Wei, Yingying Lin, Xiwei Wang, Yiwei Lai, Menghui Yin, Yanpu Chen, et al. "Concurrent binding to DNA and RNA facilitates the pluripotency reprogramming activity of Sox2." Nucleic Acids Research 48, no. 7 (February 4, 2020): 3869–87. http://dx.doi.org/10.1093/nar/gkaa067.
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Abstract Some transcription factors that specifically bind double-stranded DNA appear to also function as RNA-binding proteins. Here, we demonstrate that the transcription factor Sox2 is able to directly bind RNA in vitro as well as in mouse and human cells. Sox2 targets RNA via a 60-amino-acid RNA binding motif (RBM) positioned C-terminally of the DNA binding high mobility group (HMG) box. Sox2 can associate with RNA and DNA simultaneously to form ternary RNA/Sox2/DNA complexes. Deletion of the RBM does not affect selection of target genes but mitigates binding to pluripotency related transcripts, switches exon usage and impairs the reprogramming of somatic cells to a pluripotent state. Our findings designate Sox2 as a multi-functional factor that associates with RNA whilst binding to cognate DNA sequences, suggesting that it may co-transcriptionally regulate RNA metabolism during somatic cell reprogramming.
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Plath, Kathrin, Rupa Sridharan, Jason Tchieu, Mike J. Mason, Mark Chin, Robin Yachechko, Edward Kuoy, Qing Zhou, and Bill Lowry. "Defining the Mechanism of Transcription Factor-Induced Epigenetic Reprogramming." Blood 114, no. 22 (November 20, 2009): SCI—41—SCI—41. http://dx.doi.org/10.1182/blood.v114.22.sci-41.sci-41.
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Abstract Abstract SCI-41 The great excitement surrounding induced pluripotent stem (iPS) cells is tempered by the fact that little is known about how they are generated and why this process is so inefficient. We have set out to ask how the four transcription factors Oct4, Sox2, cMyc and Klf4 can induce pluripotency. By analyzing the role of the reprogramming factors Oct4, Sox2, Klf4 and cMyc during the initial step of reprogramming and comparing their binding and global expression in fully and partially reprogrammed cells, we previously uncovered that cMyc has a central role in the repression of the somatic cell expression program. With respect to the upregulation of the embryonic cell transcription, the four factors cooperate to activate the metabolic program, followed by binding of Oct4, Klf4 and Sox2 to genes encoding pluripotency regulators leading to the self-sustained, pluripotent state. Thus, we suggested that the factors have separable and temporal contributions to the reprogramming process. We are particularly interested in further deciphering the mechanism of reprogramming, understanding barriers of the reprogramming process, and comparing the embryonic stem cell state with the iPS cell state. Disclosures No relevant conflicts of interest to declare.
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Yang, Hua, Jiayin Mo, Qi Xiang, Peiyi Zhao, Yunting Song, Ge Yang, Kailang Wu, Yingle Liu, Weiyong Liu, and Jianguo Wu. "SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation." Viruses 12, no. 3 (February 29, 2020): 273. http://dx.doi.org/10.3390/v12030273.
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Hepatitis B virus (HBV) replication is controlled by four promoters (preS1, preS2, Cp, and Xp) and two enhancers (EnhI and EnhII). EnhII stimulates Cp activity to regulate the transcriptions of precore, core, polymerase, and pregenomic RNAs, and therefore, EnhII/Cp is essential for the regulation of HBV replication. This study revealed a distinct mechanism underlying the suppression of EnhII/Cp activation and HBV replication. On the one hand, the sex determining region Y box2 (SOX2), a transcription factor, is induced by HBV. On the other hand, SOX2, in turn, represses the expression levels of HBV RNAs, HBV core-associated DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg), thereby playing an inhibitory role during HBV replication. Further studies indicated that SOX2 bound to the EnhII/Cp DNA and repressed the promoter activation. With the deletion of the high mobility group (HMG) domain, SOX2 loses the ability to repress EnhII/Cp activation, viral RNA transcription, HBV core-associated DNA replication, HBsAg and HBeAg production, as well as fails to enter the nucleus, demonstrating that the HMG domain is required for the SOX2-mediated repression of HBV replication. Moreover, SOX2 represses HBsAg and HBeAg secretion in BALB/c mice sera, and attenuates HBV 3.5 kb RNA transcription and hepatitis B virus core protein (HBc) production in the liver tissues, demonstrating that SOX2 suppresses HBV replication in mice. Furthermore, the results revealed that the HMG domain was required for SOX2-mediated repression of HBV replication in the mice. Taken together, the above facts indicate that SOX2 acts as a new host restriction factor to repress HBV replication by binding to the viral EnhII/Cp and inhibiting the promoter activation through the HMG domain.
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Chaudhary, Sameer, Zeyaul Islam, Vijaya Mishra, Sakshi Rawat, Ghulam Md Ashraf, and Prasanna R. Kolatkar. "Sox2: A Regulatory Factor in Tumorigenesis and Metastasis." Current Protein & Peptide Science 20, no. 6 (May 20, 2019): 495–504. http://dx.doi.org/10.2174/1389203720666190325102255.
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The transcription factor Sox2 plays an important role in various phases of embryonic development, including cell fate and differentiation. These key regulatory functions are facilitated by binding to specific DNA sequences in combination with partner proteins to exert their effects. Recently, overexpression and gene amplification of Sox2 has been associated with tumor aggression and metastasis in various cancer types, including breast, prostate, lung, ovarian and colon cancer. All the different roles for Sox2 involve complicated regulatory networks consisting of protein-protein and protein-nucleic acid interactions. Their involvement in the EMT modulation is possibly enabled by Wnt/ β-catenin and other signaling pathways. There are number of in vivo models which show Sox2 association with increased cancer aggressiveness, resistance to chemo-radiation therapy and decreased survival rate suggesting Sox2 as a therapeutic target. This review will focus on the different roles for Sox2 in metastasis and tumorigenesis. We will also review the mechanism of action underlying the cooperative Sox2- DNA/partner factors binding where Sox2 can be potentially explored for a therapeutic opportunity to treat cancers.
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Blassberg, Robert, Harshil Patel, Thomas Watson, Mina Gouti, Vicki Metzis, M. Joaquina Delás, and James Briscoe. "Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation." Nature Cell Biology 24, no. 5 (May 2022): 633–44. http://dx.doi.org/10.1038/s41556-022-00910-2.
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AbstractWNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 displaces nucleosomes from regulatory elements with high-affinity SOX2 binding sites, recruiting the WNT effector TCF/β-catenin and maintaining pluripotent gene expression. Reducing SOX2 levels destabilizes pluripotency and reconfigures SOX2/TCF/β-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT-induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/β-catenin and reveal how context-specific responses to a signal are configured by the level of a transcription factor.
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Kallas, Ade, Martin Pook, Annika Trei, and Toivo Maimets. "SOX2 Is Regulated Differently from NANOG and OCT4 in Human Embryonic Stem Cells during Early Differentiation Initiated with Sodium Butyrate." Stem Cells International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/298163.
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Transcription factors NANOG, OCT4, and SOX2 regulate self-renewal and pluripotency in human embryonic stem (hES) cells; however, their expression profiles during early differentiation of hES cells are unclear. In this study, we used multiparameter flow cytometric assay to detect all three transcription factors (NANOG, OCT4, and SOX2) simultaneously at single cell level and monitored the changes in their expression during early differentiation towards endodermal lineage (induced by sodium butyrate). We observed at least four distinct populations of hES cells, characterized by specific expression patterns of NANOG, OCT4, and SOX2 and differentiation markers. Our results show that a single cell can express both differentiation and pluripotency markers at the same time, indicating a gradual mode of developmental transition in these cells. Notably, distinct regulation of SOX2 during early differentiation events was detected, highlighting the potential importance of this transcription factor for self-renewal of hES cells during differentiation.
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Ahmad, Azaz, Stephanie Strohbuecker, Claudia Scotti, Cristina Tufarelli, and Virginie Sottile. "In Silico Identification of SOX1 Post-Translational Modifications Highlights a Shared Protein Motif." Cells 9, no. 11 (November 13, 2020): 2471. http://dx.doi.org/10.3390/cells9112471.
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The transcription factor SOX1 is a key regulator of neural stem cell development, acting to keep neural stem cells (NSCs) in an undifferentiated state. Postnatal expression of Sox1 is typically confined to the central nervous system (CNS), however, its expression in non-neural tissues has recently been implicated in tumorigenesis. The mechanism through which SOX1 may exert its function is not fully understood, and studies have mainly focused on changes in SOX1 expression at a transcriptional level, while its post-translational regulation remains undetermined. To investigate this, data were extracted from different publicly available databases and analysed to search for putative SOX1 post-translational modifications (PTMs). Results were compared to PTMs associated with SOX2 in order to identify potentially key PTM motifs common to these SOXB1 proteins, and mapped on SOX1 domain structural models. This approach identified several putative acetylation, phosphorylation, glycosylation and sumoylation sites within known functional domains of SOX1. In particular, a novel SOXB1 motif (xKSExSxxP) was identified within the SOX1 protein, which was also found in other unrelated proteins, most of which were transcription factors. These results also highlighted potential phospho-sumoyl switches within this SOXB1 motif identified in SOX1, which could regulate its transcriptional activity. This analysis indicates different types of PTMs within SOX1, which may influence its regulatory role as a transcription factor, by bringing changes to its DNA binding capacities and its interactions with partner proteins. These results provide new research avenues for future investigations on the mechanisms regulating SOX1 activity, which could inform its roles in the contexts of neural stem cell development and cancer.
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Wei, Chia-Lin, Silvia K. Nicolis, Yanfen Zhu, and Miriam Pagin. "Sox2-Dependent 3D Chromatin Interactomes in Transcription, Neural Stem Cell Proliferation and Neurodevelopmental Diseases." Journal of Experimental Neuroscience 13 (January 2019): 117906951986822. http://dx.doi.org/10.1177/1179069519868224.
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In our article, we asked whether Sox2, a transcription factor important in brain development and disease, is involved in gene regulation through its action on long-range interactions between promoters and distant enhancers. Our findings highlight that Sox2 shapes a genome-wide network of promoter-enhancer interactions, acting by direct binding to these elements. Sox2 loss affects the three-dimensional (3D) genome and decreases the activity of a subset of genes involved in Sox2-bound interactions. At least one of such downregulated genes, Socs3, is critical for long-term neural stem cell maintenance. These results point to the possibility of identifying a transcriptional network downstream to Sox2, and involved in neural stem cell maintenance. In addition, interacting Sox2-bound enhancers are often connected to genes which are relevant, in man, to neurodevelopmental disease; this may facilitate the detection of functionally relevant mutations in regulatory elements in man, contributing to neural disease.
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Scaffidi, Paola, and Marco E. Bianchi. "Spatially Precise DNA Bending Is an Essential Activity of the Sox2 Transcription Factor." Journal of Biological Chemistry 276, no. 50 (October 2, 2001): 47296–302. http://dx.doi.org/10.1074/jbc.m107619200.
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Sox proteins, a subclass of high mobility group box proteins, govern cell fate decisions by acting both as classical transcription factors and architectural components of chromatin. We aimed to demonstrate that the DNA bending activity of Sox proteins is essential to regulate gene expression. We focused on mouse Sox2, which participates in the transactivation of theFgf4(fibroblastgrowthfactor4) gene in the inner cell mass of the blastocyst. We generated six substitutions in the high mobility group box of Sox2. One mutant showed a reduced DNA bending activity on theFgf4enhancer (46° instead of 80°), which resulted in more powerful transactivation compared with the wild type protein. We then selected two single-base mutations in theFgf4enhancer that make the DNA less bendable by the Sox2 protein. Again, a different DNA bend (0° and 42° instead of 80°) resulted in a different activation of transcription, but in this case reduced bending corresponded to decreased transcription. We found that the opposite effect on transcription of similar DNA bending angles is due to a 20° difference in the relative orientation of the DNA bends, proving that a correct three-dimensional geometry of enhanceosome complexes is necessary to promote transcription.
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Liu, Yongshi, Xinglin Zhang, Tao Jiang, and Ning Du. "Hypoxia-Induced Nestin Regulates Viability and Metabolism of Lung Cancer by Targeting Transcriptional Factor Nrf2, STAT3, and SOX2." Computational Intelligence and Neuroscience 2022 (August 30, 2022): 1–7. http://dx.doi.org/10.1155/2022/9811905.
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Objective. To investigate hypoxia-induced Nestin regulates lung cancer viability and metabolism by targeting transcription factors Nrf2, STAT3, and SOX2. Methods. Eighty-four cases of nonsmall cell lung cancer (nonsmall cell lung cancer, NSCLC), which had been treated from June 2020 to February 2021, were randomly selected from our clinicopathology database. Immunohistochemical staining of collected tissue cells was performed to assess the expression patterns of Nestin, STAT3, Nrf2, and SOX2. Data were quantified and statistically analyzed using one-way and two-way ANOVA tests with P < 0.05 . Results. Clinicopathological findings showed significant differences in lymph node metastasis, tissue differentiation, and histology on induction of Nestin expression; Nestin expression correlated with STAT3, Nrf2, and SOX2 expression.Nestin/STAT3/SOX2/Nrf2 are involved in angiogenesis and lung cancer development. Conclusion. Hypoxia-induced Nestin promotes the progression of nonsmall lung cancer cells by targeting the downstream transcription factors STAT3, Nrf2, and SOX2.
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Haseeb, Abdul, and Véronique Lefebvre. "The SOXE transcription factors—SOX8, SOX9 and SOX10—share a bi-partite transactivation mechanism." Nucleic Acids Research 47, no. 13 (June 13, 2019): 6917–31. http://dx.doi.org/10.1093/nar/gkz523.
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Abstract SOX8, SOX9 and SOX10 compose the SOXE transcription factor group. They govern cell fate and differentiation in many lineages, and mutations impairing their activity cause severe diseases, including campomelic dysplasia (SOX9), sex determination disorders (SOX8 and SOX9) and Waardenburg-Shah syndrome (SOX10). However, incomplete knowledge of their modes of action limits disease understanding. We here uncover that the proteins share a bipartite transactivation mechanism, whereby a transactivation domain in the middle of the proteins (TAM) synergizes with a C-terminal one (TAC). TAM comprises amphipathic α-helices predicted to form a protein-binding pocket and overlapping with minimal transactivation motifs (9-aa-TAD) described in many transcription factors. One 9-aa-TAD sequence includes an evolutionarily conserved and functionally required EΦ[D/E]QYΦ motif. SOXF proteins (SOX7, SOX17 and SOX18) contain an identical motif, suggesting evolution from a common ancestor already harboring this motif, whereas TAC and other transactivating SOX proteins feature only remotely related motifs. Missense variants in this SOXE/SOXF-specific motif are rare in control individuals, but have been detected in cancers, supporting its importance in development and physiology. By deepening understanding of mechanisms underlying the central transactivation function of SOXE proteins, these findings should help further decipher molecular networks essential for development and health and dysregulated in diseases.
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Huang, Yuanyong, Xiaoya Duan, Zhen Wang, Yimei Sun, Qingqing Guan, Li Kang, Qiao Zhang, Lan Fang, Jiwen Li, and Jiemin Wong. "An acetylation-enhanced interaction between transcription factor Sox2 and the steroid receptor coactivators facilitates Sox2 transcriptional activity and function." Journal of Biological Chemistry 297, no. 6 (December 2021): 101389. http://dx.doi.org/10.1016/j.jbc.2021.101389.
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Gil-Kulik, Paulina, Małgorzata Świstowska, Arkadiusz Krzyżanowski, Alicja Petniak, Anna Kwaśniewska, Bartosz J. Płachno, Dariusz Galkowski, Anna Bogucka-Kocka, and Janusz Kocki. "Evaluation of the Impact of Pregnancy-Associated Factors on the Quality of Wharton’s Jelly-Derived Stem Cells Using SOX2 Gene Expression as a Marker." International Journal of Molecular Sciences 23, no. 14 (July 10, 2022): 7630. http://dx.doi.org/10.3390/ijms23147630.
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SOX2 is a recognized pluripotent transcription factor involved in stem cell homeostasis, self-renewal and reprogramming. It belongs to, one of the SRY-related HMG-box (SOX) family of transcription factors, taking part in the regulation of embryonic development and determination of cell fate. Among other functions, SOX2 promotes proliferation, survival, invasion, metastasis, cancer stemness, and drug resistance. SOX2 interacts with other transcription factors in multiple signaling pathways to control growth and survival. The aim of the study was to determine the effect of a parturient’s age, umbilical cord blood pH and length of pregnancy on the quality of stem cells derived from Wharton’s jelly (WJSC) by looking at birth weight and using SOX2 gene expression as a marker. Using qPCR the authors, evaluated the expression of SOX2 in WJSC acquired from the umbilical cords of 30 women right after the delivery. The results showed a significant correlation between the birth weight and the expression of SOX2 in WJSC in relation to maternal age, umbilical cord blood pH, and the length of pregnancy. The authors observed that the younger the woman and the lower the umbilical cord blood pH, the earlier the delivery occurs, the lower the birth weight and the higher SOX2 gene expression in WJSC. In research studies and clinical applications of regenerative medicine utilizing mesenchymal stem cells derived from Wharton’s Jelly of the umbilical cord, assessment of maternal and embryonic factors influencing the quality of cells is critical.
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Underwood, Adam, Daniel T. Rasicci, David Hinds, Jackson T. Mitchell, Jacob K. Zieba, Joshua Mills, Nicholas E. Arnold, et al. "Evolutionary Landscape of SOX Genes to Inform Genotype-to-Phenotype Relationships." Genes 14, no. 1 (January 14, 2023): 222. http://dx.doi.org/10.3390/genes14010222.
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The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype–phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG (High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood–brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box associated with cardiovascular complications within European populations, and SOX7 A379V (rs143587868) within an SOXF conserved far C-terminal domain heterozygous in 0.716% of African individuals with associated eye phenotypes. This SOX data compilation builds a robust genotype-to-phenotype association for a gene family through more robust ortholog data integration.
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Ståhlberg, Anders, Martin Bengtsson, Martin Hemberg, and Henrik Semb. "Quantitative Transcription Factor Analysis of Undifferentiated Single Human Embryonic Stem Cells." Clinical Chemistry 55, no. 12 (December 1, 2009): 2162–70. http://dx.doi.org/10.1373/clinchem.2009.131433.
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Abstract Background: Human embryonic stem cells (hESCs) require expression of transcription factor genes POU5F1 (POU class 5 homeobox 1), NANOG (Nanog homeobox), and SOX2 [SRY (sex determining region Y)-box 2] to maintain their capacity for self-renewal and pluripotency. Because of the heterogeneous nature of cell populations, it is desirable to study the gene regulation in single cells. Large and potentially important fluctuations in a few cells cannot be detected at the population scale with microarrays or sequencing technologies. We used single-cell gene expression profiling to study cell heterogeneity in hESCs. Methods: We collected 47 single hESCs from cell line SA121 manually by glass capillaries and 57 single hESCs from cell line HUES3 by flow cytometry. Single hESCs were lysed and reverse-transcribed. Reverse-transcription quantitative real-time PCR was then used to measure the expression POU5F1, NANOG, SOX2, and the inhibitor of DNA binding genes ID1, ID2, and ID3. A quantitative noise model was used to remove measurement noise when pairwise correlations were estimated. Results: The numbers of transcripts per cell varied >100-fold between cells and showed lognormal features. POU5F1 expression positively correlated with ID1 and ID3 expression (P < 0.05) but not with NANOG or SOX2 expression. When we accounted for measurement noise, SOX2 expression was also correlated with ID1, ID2, and NANOG expression (P < 0.05). Conclusions: We demonstrate an accurate method for transcription profiling of individual hESCs. Cell-to-cell variability is large and is at least partly nonrandom because we observed correlations between core transcription factors. High fluctuations in gene expression may explain why individual cells in a seemingly undifferentiated cell population have different susceptibilities for inductive cues.
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Basu-Roy, U., D. Ambrosetti, R. Favaro, S. K. Nicolis, A. Mansukhani, and C. Basilico. "The transcription factor Sox2 is required for osteoblast self-renewal." Cell Death & Differentiation 17, no. 8 (May 21, 2010): 1345–53. http://dx.doi.org/10.1038/cdd.2010.57.
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Raghoebir, Lalini, Elvira Bakker, Marjon van Kempen, Anne de Munck, Siska Driegen, Sigrid Swagemakers, Ernst J. Kuipers, et al. "Transcription Factor SOX2 Affects the Developmental Fate of Intestinal Epithelium." Gastroenterology 140, no. 5 (May 2011): S—83. http://dx.doi.org/10.1016/s0016-5085(11)60338-7.
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Arter, Juliane, and Michael Wegner. "Transcription factors Sox10 and Sox2 functionally interact with positive transcription elongation factor b in Schwann cells." Journal of Neurochemistry 132, no. 4 (January 22, 2015): 384–93. http://dx.doi.org/10.1111/jnc.13013.
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Xie, Weiliang, Thomas J. Lynch, Xiaoming Liu, Scott R. Tyler, Shuyang Yu, Xinyuan Zhou, Meihui Luo, et al. "Sox2 modulates Lef-1 expression during airway submucosal gland development." American Journal of Physiology-Lung Cellular and Molecular Physiology 306, no. 7 (April 1, 2014): L645—L660. http://dx.doi.org/10.1152/ajplung.00157.2013.
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Tracheobronchial submucosal glands (SMGs) are derived from one or more multipotent glandular stem cells that coalesce to form a placode in surface airway epithelium (SAE). Wnt/β-catenin-dependent induction of lymphoid enhancer factor ( Lef-1) gene expression during placode formation is an early event required for SMG morphogenesis. We discovered that Sox2 expression is repressed as Lef-1 is induced within airway SMG placodes. Deletion of Lef-1 did not activate Sox2 expression in SMG placodes, demonstrating that Lef-1 activation does not directly inhibit Sox2 expression. Repression of Sox2 protein in SMG placodes occurred posttranscriptionally, since the activity of its endogenous promoter remained unchanged in SMG placodes. Thus we hypothesized that Sox2 transcriptionally represses Lef-1 expression in the SAE and that suppression of Sox2 in SMG placodes activates Wnt/β-catenin-dependent induction of Lef-1 during SMG morphogenesis. Consistent with this hypothesis, transcriptional reporter assays, ChIP analyses, and DNA-protein binding studies revealed a functional Sox2 DNA binding site in the Lef-1 promoter that is required for suppressing β-catenin-dependent transcription. In polarized primary airway epithelium, Wnt induction enhanced Lef-1 expression while also inhibiting Sox2 expression. Conditional deletion of Sox2 also enhanced Lef-1 expression in polarized primary airway epithelium, but this induction was significantly augmented by Wnt stimulation. Our findings provide the first evidence that Sox2 acts as a repressor to directly modulate Wnt-responsive transcription of the Lef-1 gene promoter. These studies support a model whereby Wnt signals and Sox2 dynamically regulate the expression of Lef-1 in airway epithelia and potentially also during SMG development.
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Zhang, Yuli, and Linlin Hou. "Alternate Roles of Sox Transcription Factors beyond Transcription Initiation." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5949. http://dx.doi.org/10.3390/ijms22115949.
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Sox proteins are known as crucial transcription factors for many developmental processes and for a wide range of common diseases. They were believed to specifically bind and bend DNA with other transcription factors and elicit transcriptional activation or repression activities in the early stage of transcription. However, their functions are not limited to transcription initiation. It has been showed that Sox proteins are involved in the regulation of alternative splicing regulatory networks and translational control. In this review, we discuss the current knowledge on how Sox transcription factors such as Sox2, Sry, Sox6, and Sox9 allow the coordination of co-transcriptional splicing and also the mechanism of SOX4-mediated translational control in the context of RNA polymerase III.
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Liu, Shaofeng, Yunfeng Wang, Yongtian Lu, Wen Li, Wenjing Liu, Jun Ma, Fuqin Sun, et al. "The Key Transcription Factor Expression in the Developing Vestibular and Auditory Sensory Organs: A Comprehensive Comparison of Spatial and Temporal Patterns." Neural Plasticity 2018 (October 15, 2018): 1–9. http://dx.doi.org/10.1155/2018/7513258.
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Inner ear formation requires that a series of cell fate decisions and morphogenetic events occur in a precise temporal and spatial pattern. Previous studies have shown that transcription factors, including Pax2, Sox2, and Prox1, play important roles during the inner ear development. However, the temporospatial expression patterns among these transcription factors are poorly understood. In the current study, we present a comprehensive description of the temporal and spatial expression profiles of Pax2, Sox2, and Prox1 during auditory and vestibular sensory organ development in mice. Using immunohistochemical analyses, we show that Sox2 and Pax2 are both expressed in the prosensory cells (the developing hair cells), but Sox2 is later restricted to only the supporting cells of the organ of Corti. In the vestibular sensory organ, however, the Pax2 expression is localized in hair cells at postnatal day 7, while Sox2 is still expressed in both the hair cells and supporting cells at that time. Prox1 was transiently expressed in the presumptive hair cells and developing supporting cells, and lower Prox1 expression was observed in the vestibular sensory organ compared to the organ of Corti. The different expression patterns of these transcription factors in the developing auditory and vestibular sensory organs suggest that they play different roles in the development of the sensory epithelia and might help to shape the respective sensory structures.
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Kelberman, Daniel, and Mehul Tulsidas Dattani. "Hypothalamic and pituitary development: novel insights into the aetiology." European Journal of Endocrinology 157, suppl_1 (August 2007): S3—S14. http://dx.doi.org/10.1530/eje-07-0156.
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The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.
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Nakatake, Yuhki, Nobutaka Fukui, Yuko Iwamatsu, Shinji Masui, Kadue Takahashi, Rika Yagi, Kiyohito Yagi, et al. "Klf4 Cooperates with Oct3/4 and Sox2 To Activate the Lefty1 Core Promoter in Embryonic Stem Cells." Molecular and Cellular Biology 26, no. 20 (September 5, 2006): 7772–82. http://dx.doi.org/10.1128/mcb.00468-06.
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ABSTRACT Although the POU transcription factor Oct3/4 is pivotal in maintaining self renewal of embryonic stem (ES) cells, little is known of its molecular mechanisms. We previously reported that the N-terminal transactivation domain of Oct3/4 is required for activation of Lefty1 expression (H. Niwa, S. Masui, I. Chambers, A. G. Smith, and J. Miyazaki, Mol. Cell. Biol. 22:1526-1536, 2002). Here we test whether Lefty1 is a direct target of Oct3/4. We identified an ES cell-specific enhancer upstream of the Lefty1 promoter that contains binding sites for Oct3/4 and Sox2. Unlike other known Oct3/4-Sox2-dependent enhancers, however, this enhancer element could not be activated by Oct3/4 and Sox2 in differentiated cells. By functional screening of ES-specific transcription factors, we found that Krüppel-like factor 4 (Klf4) cooperates with Oct3/4 and Sox2 to activate Lefty1 expression, and that Klf4 acts as a mediating factor that specifically binds to the proximal element of the Lefty1 promoter. DNA microarray analysis revealed that a subset of putative Oct3/4 target genes may be regulated in the same manner. Our findings shed light on a novel function of Oct3/4 in ES cells.
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Li, Qi, Jing Deng, Juan Yang, Tao Xu, Xinyuan Yu, Jinxian Yuan, Rong Li, Jie Fu, Qian Jiang, and Yangmei Chen. "Effects of P-gpMAbNano-structured material nanoparticles on epilepsy and expression of SRY-related HMG Box 21 in epilepsy." Materials Express 10, no. 4 (April 1, 2020): 585–93. http://dx.doi.org/10.1166/mex.2020.1664.
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SRY-related HMG box (SOX)21, one of the most highly expressed transcription inhibitors in the central nervous system (CNS), is involved in neurogenesis-related transcription and proliferation, which are associated with certain neurological disorders. However, it is the role of SOX21 in the pathogenesis of epilepsy remains unclear. In this study, our aim was to examine the expression and function of SOX21 in patients with temporal lobe epilepsy (TLE), as well as pentylenetetrazol (PTZ)-kindled rats, and to identify the possible roles of SOX21 in epileptogenesis. We found that SOX21 localized in neurons is upregulated, especially in TLE patients. SOX21 is present in the hippocampus or adjacent temporal cortex in the PTZ-kindled epileptic rat model. In addition, the P-gpMAbNano-structured material (PNM) nanoparticles carrying anti-epileptic drugs (AEDs) were injected into the epileptic model rats using an intravenous injection. The expression of tumor necrosis factor peptide in the rats was detected to verify whether the drug-carrying nanoparticles could bypass macrophages and reach the target for treatment. We also found an interaction between SOX21 and SOX2 in PTZ-kindled rats. These results indicate that SOX21 is mainly located in neurons and may regulate the pathogenesis of epilepsy, possibly in association with SOX2. Moreover, PNM nanoparticles equipped with AEDs can reach the target through macrophages in vivo, providing a new approach for the clinical treatment of epilepsy.
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Pagin, Miriam, Mattias Pernebrink, Mattia Pitasi, Federica Malighetti, Chew-Yee Ngan, Sergio Ottolenghi, Giulio Pavesi, Claudio Cantù, and Silvia K. Nicolis. "FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes." Cells 10, no. 7 (July 12, 2021): 1757. http://dx.doi.org/10.3390/cells10071757.
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The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSC’s long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a “mixed” neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the “neuronal” genes are bound by both SOX2 and AP1.
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Carvalho, Luciani, Claudia Chang, Berenice Mendoca, and Juliana Marques. "OR08-1 PROP1 Is Not Essential For Pituitary Cells Terminal Differentiation." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A452. http://dx.doi.org/10.1210/jendso/bvac150.940.
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Abstract Introduction The pituitary gland controls several mechanisms as metabolism, growth, and reproduction, in response to hypothalamic stimuli. The adequate temporal/ spatial expression of transcription factors is mandatory for a normal pituitary development. PROP1 transcription factor is widely known as a key pituitary regulator. Pathogenic variants in the PROP1 gene are the main familial causes of hypopituitarism accounting for about 54% of the cases. Aim To characterize the expression of genes involved in pituitary cells determination and specification during pituitary high demand period such as sexual maturation compared to adulthood in the Ames mice. Methods Weight and naso-anal length were measured. Pituitary glands were collected from 5 wild type (WT) and 5 prop1 mutant (Mut) animals with 30 (P30), 40, (P40), and 60 (P60) days after birth. RT-qPCR was performed to analyze the pituitary transcription factors Sox2, Sox3, Hesx1, Otx2, and genes codifying the hormones GH, TSH, LH/ FSH, CGA, and PRL by SYBR® Green (QIAGEN, Valencia, CA). They were normalized by endogenous genes and performed in triplicate. The target genes relative quantification was performed using the mutant related to its age paired wild type as a calibrator and the results were expressed as fold change. Immunofluorescence of SOX2 (ab97959, Abcam, UK) (1: 1600) and pituitary hormones GH, LH, and FSH (1: 250) were done in pituitaries at P60 and its aged paired control, stained with propidium iodide (1: 1000) for nucleus and the secondary antibody Alexa FluorÒ488 (ab150077, Abcam, UK) (1: 1000). Results All mutant mice presented decreased weight and naso-anal length at the three analyzed periods. The expression of the pituitary stem/ progenitor cell marker Sox2 was increased at P30 and P60 and decreased at P40. Sox3 was increased at P30 and decreased at P40 and P60. Hesx1 was increased at P30 and P60 and decreased at P40. Otx2 was increased at all periods. At P30 the genes codifying pituitary hormones was decreased, except for Tsh and Fsh. At P40 it was observed increased expression of the genes codifying Gh, Lh, Fsh and Prl, while Tsh and Cga expression was reduced. At P60 all pituitary hormones codifying genes presented decreased expression. The immunofluorescence at P60 showed increased expression of SOX2, similar expression of FSH, and decreased expression of GH and LH related to their age paired WT. Conclusion Despite the absence of PROP1, Hesx1 is downregulated at P40. Pituitary cell subtype differentiation and hormonal production is observed at transcriptional and protein levels, showing that pituitary cells can differentiate and produce hormones in the absence of Prop1. The recovery of pituitary capacity to differentiate in mutant suggests the involvement of another factor in the pituitary cell differentiation pathway that could compensate the lack of Prop1. Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.
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Buescher, Marita, Fook Sion Hing, and William Chia. "Formation of neuroblasts in the embryonic central nervous system of Drosophila melanogaster is controlled by SoxNeuro." Development 129, no. 18 (September 15, 2002): 4193–203. http://dx.doi.org/10.1242/dev.129.18.4193.
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Sox proteins form a family of HMG-box transcription factors related to the mammalian testis determining factor SRY. Sox-mediated modulation of gene expression plays an important role in various developmental contexts. Drosophila SoxNeuro, a putative ortholog of the vertebrate Sox1, Sox2 and Sox3 proteins, is one of the earliest transcription factors to be expressed pan-neuroectodermally. We demonstrate that SoxNeuro is essential for the formation of the neural progenitor cells in central nervous system. We show that loss of function mutations of SoxNeuro are associated with a spatially restricted hypoplasia: neuroblast formation is severely affected in the lateral and intermediate regions of the central nervous system, whereas ventral neuroblast formation is almost normal. We present evidence that a requirement for SoxNeuro in ventral neuroblast formation is masked by a functional redundancy with Dichaete, a second Sox protein whose expression partially overlaps that of SoxNeuro. Genetic interactions of SoxNeuro and the dorsoventral patterning genes ventral nerve chord defective and intermediate neuroblasts defective underlie ventral and intermediate neuroblast formation. Finally, the expression of the Achaete-Scute gene complex suggests that SoxNeuro acts upstream and in parallel with the proneural genes.
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Stolzenburg, Sabine, Marianne G. Rots, Adriana S. Beltran, Ashley G. Rivenbark, Xinni Yuan, Haili Qian, Brian D. Strahl, and Pilar Blancafort. "Targeted silencing of the oncogenic transcription factor SOX2 in breast cancer." Nucleic Acids Research 40, no. 14 (May 4, 2012): 6725–40. http://dx.doi.org/10.1093/nar/gks360.
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Tani, Yasuyo, Yoshimitsu Akiyama, Hiroshi Fukamachi, Kazuyoshi Yanagihara, and Yasuhito Yuasa. "Transcription factor SOX2 up-regulates stomach-specific pepsinogen A gene expression." Journal of Cancer Research and Clinical Oncology 133, no. 4 (November 28, 2006): 263–69. http://dx.doi.org/10.1007/s00432-006-0165-x.
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Mack, Stephen. "EPEN-31. Developmental and Oncogenic Transcription Factor Circuits as Dependencies in Ependymoma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i46. http://dx.doi.org/10.1093/neuonc/noac079.167.
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Abstract Brain tumors are the most common cause of cancer death in children. ZFTA-RELA gene fusion is one the most potent drivers of cancer and is sufficient to induce tumors when expressed during brain development. ZFTA-RELA (denoted ZRFUS) fusion is the most frequent events that occurs in an aggressive childhood brain tumor called ependymoma (> 70% of cases). ZFTA recruits RELA to novel DNA binding sites and is necessary to activate ependymoma oncogene transcription. There are currently no targetable treatments for ependymoma, thus studying the mechanisms that regulate ZRFUS oncogenic programs may yield opportunities to develop effective therapies. To study proteins that regulate gene expression programs in brain cancer, the Mack lab and others have comprehensively characterized the active chromatin landscapes of several adult and pediatric brain cancers. This genome-wide analysis has identified highly active TFs, termed core regulatory circuit (CRC) TFs that govern gene expression programs such as MYC, GLI2, SOX2, and OLIG1/2, previously described in brain tumors such as glioblastoma and medulloblastoma. Critically, a glial cell fate specification TF, SOX9, showed the highest levels of activity in ependymoma. A functional RNA interference screen of CRC TFs prioritized SOX9 as the top cancer dependency gene required for ZRFUS ependymoma cell proliferation. To study ZRFUS ependymoma, we developed one of the first genetic mouse models of the disease, and show in preliminary data, that SOX9 knockout abolishes tumor initiation. Surprisingly, SOX9 KO has no impact on tumor initiation in an aggressive glioma model, suggesting tumor-specific contributions of SOX9. This concept is supported by our data that shows SOX9 co-recruitment to a vast majority of ZRFUS binding sites in the genome. Our data supports that SOX9 regulates ZFTA-RELA target cistrome; presenting a potential pathway that may be explored for therapeutic benefit.
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Feng, Ruopeng, and Jinhua Wen. "Overview of the roles of Sox2 in stem cell and development." Biological Chemistry 396, no. 8 (August 1, 2015): 883–91. http://dx.doi.org/10.1515/hsz-2014-0317.
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Abstract Sox2 is well known for its functions in embryonic stem (ES) cell pluripotency, maintenance, and self-renewal, and it is an essential factor in generating inducible pluripotent stem (iPS) cells. It also plays an important role in development and adult tissue homeostasis of different tissues, especially the central nervous system. Increasing evidence has shown that aging is a stemness-related process in which Sox2 is also implicated as a key player, especially in the neural system. These distinct roles that Sox2 plays involve delicate regulatory networks consisting of other master transcription factors, microRNAs and signaling pathways. Additionally, the expression level of Sox2 can also be modulated transcriptionally, translationally or post-translationally. Here we will mainly review the roles of Sox2 in stem cell related development, homeostasis maintenance, aging processes, and the underlying molecular mechanisms involved.
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Ambrosetti, D. C., C. Basilico, and L. Dailey. "Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites." Molecular and Cellular Biology 17, no. 11 (November 1997): 6321–29. http://dx.doi.org/10.1128/mcb.17.11.6321.
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Octamer binding and Sox factors are thought to play important roles in development by potentiating the transcriptional activation of specific gene subsets. The proteins within these factor families are related by the presence of highly conserved DNA binding domains, the octamer binding protein POU domain or the Sox factors HMG domain. We have previously shown that fibroblast growth factor 4 (FGF-4) gene expression in embryonal carcinoma cells requires a synergistic interaction between Oct-3 and Sox2 on the FGF-4 enhancer. Sox2 and Oct-3 bind to adjacent sites within this enhancer to form a ternary protein-DNA complex (Oct-3*) whose assembly correlates with enhancer activity. We now demonstrate that increasing the distance between the octamer and Sox binding sites by base pair insertion results in a loss of enhancer function. Significantly, those enhancer "spacing mutants" which failed to activate transcription were also compromised in their ability to form the Oct* complexes even though they could still bind both Sox2 and the octamer binding proteins, suggesting that a direct interaction between Sox2 and Oct-3 is necessary for enhancer function. Consistent with this hypothesis, Oct-3 and Sox2 can participate in a direct protein-protein interaction in vitro in the absence of DNA, and both this interaction and assembly of the ternary Oct* complexes require only the octamer protein POU and Sox2 HMG domains. Assembly of the ternary complex by these two protein domains occurs in a cooperative manner on FGF-4 enhancer DNA, and the loss of this cooperative interaction contributes to the defect in Oct-3* formation observed for the enhancer spacing mutants. These observations indicate that Oct-3* assembly results from protein-protein interactions between the domains of Sox2 and Oct-3 that mediate their binding to DNA, but it also requires a specific arrangement of the binding sites within the FGF-4 enhancer DNA. Thus, these results define one parameter that is fundamental to synergistic activation by Sox2 and Oct-3 and further emphasize the critical role of enhancer DNA sequences in the proper assembly of functional activation complexes.
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Rassouli, Fatemeh B., Maryam M. Matin, Ahmad Reza Bahrami, Kamran Ghaffarzadegan, Sajjad Sisakhtnezhad, Hamid Cheshomi, and Fatemeh Abbasi. "SOX2 Expression in Gastrointestinal Cancers of Iranian Patients." International Journal of Biological Markers 30, no. 3 (July 2015): 315–20. http://dx.doi.org/10.5301/jbm.5000137.
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Purpose Gastrointestinal (GI) malignancies are among the 5 most common cancers in Iran, and their high associated mortality rates are attributable to late diagnosis and poor treatment options. SOX2, a transcription factor necessary for maintenance and induction of pluripotency and self-renewal, has been identified as a lineage-survival oncogene in several cancers. In the present study, we examined SOX2 expression in esophageal squamous cell carcinoma (ESCC), gastric adenocarcinoma and colon squamous cell carcinoma (SCC), as well as normal GI tissues, in Iranian patients. Methods To elucidate the role of SOX2 in GI carcinogenesis, formalin-fixed tissues were analyzed using immunohistochemistry (IHC), while frozen ESCC samples were studied by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results IHC studies indicated presence of SOX2+ cells in a subset of cancerous and normal tissues of stomach and colon, while no significant difference was observed between groups, and no correlation was found between SOX2 expression and tumors grades. Nevertheless, studying ESCC samples with IHC and qRT-PCR revealed overexpression of SOX2 in comparison with normal adjacent tissues. Conclusions The present results are in line with other studies and indicate SOX2 up-regulation in ESCC; however, due to our small sample size and contradictory reports, more research is needed to determine the importance of SOX2 in GI cancers.
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Dittmer, Angela, and Jürgen Dittmer. "Carcinoma-Associated Fibroblasts Promote Growth of Sox2-Expressing Breast Cancer Cells." Cancers 12, no. 11 (November 19, 2020): 3435. http://dx.doi.org/10.3390/cancers12113435.
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CAFs (Carcinoma-associated fibroblasts) play an important role in cancer progression. For instance, they promote resistance to anti-estrogens, such as fulvestrant. Here, we show that, in ERα-positive breast cancer cell lines, the cocktail of factors secreted by CAFs (CAF-CM) induce the expression of the embryonal stem cell transcription factor Sox2 (sex determining region Y (SRY)-box 2). Long-term exposure to CAF-CM was able to give rise to very high Sox2 levels both in the absence and presence of fulvestrant. IL-6 (interleukin-6), a major component of CAF-CM, failed to raise Sox2 expression. In MCF-7 sublines established in the presence of CAF-CM, almost all cells showed Sox2 expression, whereas long-term treatment of T47D cells with CAF-CM resulted in a ~60-fold increase in the proportions of two distinct populations of Sox2 high and low expresser cells. Exposure of BT474 cells to CAF-CM raised the fraction of Sox2 high expresser cells by ~3-fold. Cell sorting based on CD44 and CD24 expression or ALDH (aldehyde dehydrogenase) activity revealed that most Sox2 high expresser cells were not CD44hi/CD24lo- or ALDH-positive cells suggesting that they were not CSCs (cancer stem cells), though CD44 played a role in Sox2 expression. Functionally, Sox2 was found to protect CAF-CM-treated cells against apoptosis and to allow higher growth activity in the presence of fulvestrant. Mechanistically, the key drivers of Sox2 expression was found to be STAT3 (Signal transducer and activator of transcription 3), Bcl-3 (B-cell lymphoma 3) and the PI3K (Phosphoinositide 3-kinase)/AKT pathway, whose activities/expression can all be upregulated by CAF-CM. These data suggest that CAF-CM induces Sox2 expression in non-CSCs by activating proteins involved in growth control and drug resistance, leading to higher protection against apoptosis.
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DRAKULIC, DANIJELA, JELENA MARJANOVIC VICENTIC, MARIJA SCHWIRTLICH, JELENA TOSIC, ALEKSANDAR KRSTIC, ANDRIJANA KLAJN, and MILENA STEVANOVIC. "The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1." Anais da Academia Brasileira de Ciências 87, no. 1 (March 6, 2015): 389–404. http://dx.doi.org/10.1590/0001-3765201520140352.
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The altered expression of the SOX2 transcription factor is associated with oncogenic or tumor suppressor functions in human cancers. This factor regulates the migration and invasion of different cancer cells. In this study we investigated the effect of constitutive SOX2 overexpression on the migration and adhesion capacity of embryonal teratocarcinoma NT2/D1 cells derived from a metastasis of a human testicular germ cell tumor. We detected that increased SOX2 expression changed the speed, mode and path of cell migration, but not the adhesion ability of NT2/D1 cells. Additionally, we demonstrated that SOX2 overexpression increased the expression of the tumor suppressor protein p53 and the HDM2 oncogene. Our results contribute to the better understanding of the effect of SOX2 on the behavior of tumor cells originating from a human testicular germ cell tumor. Considering that NT2/D1 cells resemble cancer stem cells in many features, our results could contribute to the elucidation of the role of SOX2 in cancer stem cells behavior and the process of metastasis.
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Kaufhold, Samantha, Hermes Garban, and Benjamin Bonavida. "In silico Tissue-Based Expression Analysis of YY1 and Cancer Stem Cell (CSC) Transcription Factors in Hematological Malignancies: Unraveling New Therapeutic Targets." Blood 126, no. 23 (December 3, 2015): 4814. http://dx.doi.org/10.1182/blood.v126.23.4814.4814.
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Abstract Introduction: Yin Yang 1 (YY1) is a transcription factor, (a 44 kDa protein), ubiquitously expressed in many tissues and cancers. YY1 exerts multiple functions, including transcriptional regulation of many genes involved in cell proliferation, chromatin remodeling, drug and immune resistance, and metastasis [1].Cancer stem cells (CSCs) are a small subset of cancer cells that drive tumorigenesis and metastasis and are considered to be resistant to cytotoxic therapies; they are pluripotent and capable of self-renewal. Objective: To determine if YY1 is a transcription factor that regulates CSCs. Hypothesis: We hypothesized that YY1 may be overexpressed in CSCs, and its expression may be coordinated with the expression of CSC transcription factors. The overexpressions and activities of SOX2, OCT4 (POU5F1), BMI1 and NANOG are characteristics of the CSC phenotype in many cancers. Methods: The above hypothesis was tested by comparing the expression patterns of the four CSC markers and YY1 in hematological malignancies. The data were collected from the Human Protein Atlas proteomics database, and only high and medium expressions were considered positive. Results: From the data that were collected, the overall percentage of positively stained cells was determined. Our preliminary findings demonstrated that there was a strong correlation between the expression patterns of YY1 and BMI1, some correlation between YY1, OCT4 and SOX2, and no correlation between YY1 and NANOG, which was usually underexpressed. The interactomes of OCT4 and SOX2 are important parts of the regulatory network of hESCs. Further, multiple DNA binding proteins, including YY1, are enriched in both interactomes [2]. Conclusion: The findings suggest strongly that CSCs may overexpress YY1 in coordination with the overexpressions of SOX2, BMI1, and OCT4. They further suggest that YY1 may constitute a CSC biomarker, and they revealed potential therapeutic targets. [1] Critical Reviews™ in Oncogenesis Volume 16, 2011 [2] Gao F et al., Sci Report 3:1588,2013. Disclosures No relevant conflicts of interest to declare.
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Stincic, Todd L., Patrick W. Keeley, Benjamin E. Reese, and W. Rowland Taylor. "Bistratified starburst amacrine cells in Sox2 conditional knockout mouse retina display ON and OFF responses." Journal of Neurophysiology 120, no. 4 (October 1, 2018): 2121–29. http://dx.doi.org/10.1152/jn.00322.2018.
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Cell-intrinsic factors, in conjunction with environmental signals, guide migration, differentiation, and connectivity during early development of neuronal circuits. Within the retina, inhibitory starburst amacrine cells (SBACs) comprise ON types with somas in the ganglion cell layer (GCL) and dendrites stratifying narrowly in the inner half of the inner plexiform layer (IPL) and OFF types with somas in the inner nuclear layer (INL) and dendrites stratifying narrowly in the outer half of the IPL. The transcription factor Sox2 is crucial to this subtype specification. Without Sox2, many ON-type SBACs destined for the GCL settle in the INL while many that reach the GCL develop bistratified dendritic arbors. This study asked whether ON-type SBACs in Sox2-conditional knockout retinas exhibit selective connectivity only with ON-type bipolar cells or their bistratified morphology allows them to connect to both ON and OFF bipolar cells. Physiological data demonstrate that these cells receive ON and OFF excitatory inputs, indicating that the ectopically stratified dendrites make functional synapses with bipolar cells. The excitatory inputs were smaller and more transient in Sox2-conditional knockout compared with wild type; however, inhibitory inputs appeared largely unchanged. Thus dendritic stratification, rather than cellular identification, may be the major factor that determines ON vs. OFF connectivity. NEW & NOTEWORTHY Conditional knockout of the transcription factor Sox2 during early embryogenesis converts a monostratifying starburst amacrine cell into a bistratifying starburst cell. Here we show that these bistratifying starburst amacrine cells form functional synaptic connections with both ON and OFF bipolar cells. This suggests that normal ON vs. OFF starburst connectivity may not require distinct molecular specification. Proximity alone may be sufficient to allow formation of functional synapses.
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Kervarrec, Thibault, Mahtab Samimi, Sonja Hesbacher, Patricia Berthon, Marion Wobser, Aurélie Sallot, Bhavishya Sarma, et al. "Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells." Cancers 12, no. 7 (July 21, 2020): 1989. http://dx.doi.org/10.3390/cancers12071989.
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Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.