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Sox2

Sox2 Book
Author : Hisato Kondoh,Robin Lovell-Badge
Publisher : Academic Press
Release : 2015-08-24
ISBN : 0128004207
Language : En, Es, Fr & De

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Book Description :

Sox2: Biology and Role in Development and Disease offers a thorough discussion of the important role of Sox2 in cellular and developmental processes, aimed at facilitating greater understanding of how Sox2 functions across different disciplines. The book discusses the basic biology of Sox2 to help establish the critical foundational knowledge necessary for deeper molecular and functional analysis. The book also provides insight into how the Sox2 transcription factor plays a key role in pluripotency induction, maintenance, and development. Helpful as a tool to organize new research projects, the book assists with preparing lessons, seminars, and thesis or research papers, thereby circumventing the need to spend hours searching through journal databases. A single source for the basic biology of Sox2, Sox2: Biology and Its Role in Development and Disease provides information on networks, gene regulation, and regulatory function in a number of cell types and tissues types. Discusses the important role of Sox2 in cellular and developmental processes Facilitates a greater understanding of how Sox2 functions across different disciplines Assists in identifying, circumventing and modifying the dynamics of Sox2 in cell types Provides greater understanding of the structure of Sox2 and its gene networks Identifies aspects of phenotypic spectrum uncovered following greater understanding of Sox2 during development

The Role of SOX2 in Human Embryonic Stem Cells

The Role of SOX2 in Human Embryonic Stem Cells Book
Author : Helen Fong
Publisher : Unknown
Release : 2011
ISBN : 9781124674698
Language : En, Es, Fr & De

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Book Description :

SOX2 is a transcription factor critical for maintenance of the stem cell state. It plays a major role in the development of the central nervous system (CNS), as it is required for the proliferation and maintenance of neural stem cells as well as neurogenesis. In this work, I show that SOX2 is a crucial factor for the maintenance of pluripotency and self-renewal in hES cells and further elucidate its role in the regulation of the survival gene, TRKC. I also present evidence that SOX2 can interact with the POU transcription factor OCT1 in the regulation of TRKC, demonstrating a novel SOX2 protein-protein interaction in human embryonic stem (hES) cells. By using siRNA to reduce levels of SOX2 expression, I find that loss of SOX2 significantly affects the morphology of hES cells as well as downregulates markers of pluripotent hES cells, OCT4, TRA-1-81, SSEA-3, and SSEA-4. In addition to reducing SOX2 levels, I knocked down expression of OCT4 and NANOG and find that the expression of the three factors depends on each other to maintain the stem cell state. Loss of SOX2 also causes hES cells to differentiate into trophectoderm, as well as affect a number of downstream target genes, which may be important for the stem cell state. I also demonstrate that SOX2 can regulate the TRKC gene, a gene important for the survival of single hES cells. Through RNAi of SOX2, I found the expression of TRKC to be significantly downregulated indicating that SOX2 has a regulatory effect on TRKC gene expression. SOX2 is able to physically bind to a particular SOX2 binding motif on the regulatory region of the gene and efficiently drive expression. I also present data that suggests SOX2 can interact with the OCT1 transcription factor to possibly regulate TRKC. This data is novel in hES cells, indicating that there may be many undiscovered interactions between SOX2 and other transcription factors.

Sox2 Defines Distinct Functional Classes of Stem Cells

Sox2 Defines Distinct Functional Classes of Stem Cells Book
Author : Kevin Allen D'Amour
Publisher : Unknown
Release : 2002
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Sox2 Defines Distinct Functional Classes of Stem Cells book written by Kevin Allen D'Amour, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Function of Sox2 as a Transcriptional Repressor

Function of Sox2 as a Transcriptional Repressor Book
Author : Yu-Ru Liu
Publisher : Unknown
Release : 2011
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Sox2 is one of the earliest known transcription factors to be expressed during development of the nervous system (Rex et al., 1997; Silvia Brunelli, 2003; Wang et al., 2006b; Dee et al., 2008). Ectodermal cells expressing Sox2 have the potential to differentiate into nerve cells. Cells expressing Sox2 are specified to a neural fate during neural induction. Sox2 belongs to the SoxB1 family, comprising Sox1, Sox2 and Sox3, which are generally considered to activate specific target genes, whereas, the SoxB2 group, Sox14 and Sox21, act as transcriptional repressors (Uchikawa, Kamachi, & Kondoh, 1999). However, Sox2 has also been demonstrated to act as a repressor (Kopp et al., 2008) which implies that Sox2 could have a dual-function in vivo. Previous studies indicated that the HMG box-containing protein, Tcf/Lef, interacts with the transcriptional co-repressor, Groucho (Helen Brantjes, 2001). We therefore set out to determine if interaction with the Groucho co-repressor could also explain the repressor ability of Sox2. In this study, we have examined the interaction between Sox2 and Groucho using nuclear translocation, yeast-two-hybrid and co-immunoprecipitation assays. The data suggest that Sox2 interacts with Groucho through a C-terminal, engrailed-like motif. The effect of Groucho on Sox2 function was measured using a luciferase reporter assay. The transcriptional activation activity of Sox2 was repressed after co-expressing with Groucho. To address the biological function of Sox2-Groucho interaction, a loss-of-repressor-function mutant of Sox2 was created by point mutating the essential engrailed-like motif. Analysis in Zebrafish embryos indicated that the of loss-of-repressor-function mutant of Sox2 (Sox2LQY/AAA) lost the ability to repress the expression of chordin. In human neural stem cells, Affymetrix arrays revealed that 676 genes were activated and 786 genes were repressed by Sox2 overexpression. Within the genes that were repressed by Sox2, approximatly 7% were less repressed by Sox2LQY/AAA. Together, these data suggest that Sox2 functions not only as a transcriptional activator but also as a repressor through interacting with the corepressor Groucho. However, because only 7% of the repressed genes were affected by the Sox2LQY/AAA mutant, this suggests that there are other mechanisms involved in Sox2 transcriptional repressor function.

Sox2 and Inner Ear Development

Sox2 and Inner Ear Development Book
Author : Junchang Li
Publisher : Unknown
Release : 2017-01-27
ISBN : 9781361360958
Language : En, Es, Fr & De

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Book Description :

This dissertation, "Sox2 and Inner Ear Development" by Junchang, Li, 李俊畅, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Sox2, a HMG box transcription factor, is well known for its role in stem cell maintenance, iPS (induced pluripotent stem cell) induction, and development of neural tissues such as central nervous system and sensory organs. Sox2 has been demonstrated to be essential for the development of inner ear sensory patches. It has been shown that Sox2 is under the regulation of multiple regulatory elements to obtain a tissue specific manner. Two allelic mouse mutants, yellow submarine (Ysb) and Light coat and circling (Lcc) show hearing and balance impairments with different severity. They were made by random insertions of a transgene (pAA2) and X-ray irradiation respectively. Ysb and Lcc are both localized to chromosome 3 and involve complex chromosomal rearrangements. The Sox2 coding region is intact in the mutants, while the Sox2 expression in the otocyst is greatly reduced in Ysb and totally lost in Lcc, which indicates the tissue specific reduction of Sox2 may be due to the rearrangement of Sox2 regulatory element(s). Since Sox2 null mutants die before implantation, the two Sox2 inner ear mutants are valuable models for studying Sox2 knock down (Ysb) and Sox2 knock out (Lcc) condition in the inner ear. To understand the molecular basis behind Sox2 regulation in the inner ear, this project aims to identify the Sox2 otic regulatory elements, and potential Sox2 downstream targets involved in the development of inner ear. Previous work has indicated that Nop1 and Nop2 are the otic specific regulatory elements of Sox2 in chicken ear. In this project, transgenic mice were generated using Nop1-Nop2, and the result showed Nop1-Nop2 could drive Sox2 expression to the dorsal side of the otiv vesicle, which is different from the endogenous Sox2 expression pattern. Therefore, Nop1 and Nop2 may require other regulatory element(s) to gain a correct regulatory pattern. BAC(RP23-335P23), which contained the DNA sequences close to Ysb integration site 1 was also been tested in transgenic mice. Interestingly, the result showed that BAC(RP23-335P23) could drive Sox2 expression to the ventral side of the otic vesicle, indicating that this BAC may contain the Sox2 otic regulatory element(s). In this project, the binding relationship between Sox2 protein and Math1 enhancer has also been identified using chromatin immunoprecipitation (Ch-IP). Results showed that Sox2 could bind to Math1 enhancer A in the inner ear cochlea. So Sox2 may regulate Math1 through binding to Math1 enhancer A in inner ear development. Using a bioinformatics approach, potential Sox2 target genes in inner ear development have been identified from public microarray data on E9 to E15 inner ear tissue by the presence of conserved Sox2 binding sites. Among these potential targets, 4 genes (Itga6, Erbb3, Sox10 and Mycn) have been selected based on their known functions. Their expression patterns in the cochlea of wild type, Ysb and Lcc were verified. The identification of Sox2 downstream target genes using a bioinformatics approach will help us to understand the molecular basis of Sox2 regulation, and also understand the role of Sox2 in the inner ear development. DOI: 10.5353/th_b4961745 Subjects: Transcription factors Labyrinth (Ear) - Growth

The Role of SOX2 in Colon Cancer Progression

The Role of SOX2 in Colon Cancer Progression Book
Author : Debasish Boral (‡e author)
Publisher : Unknown
Release : 2014
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

SRY (sex determining region Y)-box 2 (SOX2) is one the embryonic stem cell transcription factors that is capable of reprogramming adult differentiated cells into an induced pluripotent cell. SOX2 is amplified in various types of epithelial cancers and its high its expression correlates with poor prognosis and decreased patient survival. Aberrant Wnt signaling drives the colo-rectal carcinogenic process and is a major determinant of the disease outcome. This study demonstrates that SOX2 counteracts Wnt driven tumor cell proliferation and maintains quiescence in a sub-population of Colo-Rectal Cancer (CRC) cells. High SOX2 expression is found in a sub-group of CRC patients with advanced disease. High SOX2 expression coupled with low Wnt activity was found in SW620 metastatic CRC cell line, while the opposite was true for the isogenic SW480 primary tumor cell line. SOX2 silencing increased Wnt activity and enhanced the oncogenic potential of SW620 cells in vitro and in vivo while over-expression had opposite effects in SW480 cells. SOX2 up-regulates the expression of PTPRK and PHLPP2 protein phosphatase genes which in turn attenuates Wnt activity by interfering with Protein Kinase A, B and C mediated beta catenin phosphorylation at Serine 552 and 675 amino acid residues thereby diminishing its nuclear sequestration and transcriptional activation. Thus SOX2 mitigates growth factor mediated Wnt activation in CRC cells and inhibits cellular proliferation so that these cells are forced to change their oncogene addiction. In effect, high SOX2 expression causes clonal evolution of APC mutant CRC cells from a state of high Wnt dependency to a state of low Wnt dependency in the process making such cells resistant to Wnt inhibitor therapy. Enhanced SOX2 transcriptional activity was associated with increased proportion of cancer cells in G0 -G1 phase of cell cycle. Changing SOX2 protein levels in cells had a direct correlation with mRNA levels of RBL2-HUMAN and CDKN2B genes, which serve as regulators of G0 and G1 respectively. SOX2 was shown to physically bind and to the promoter region of these two genes and enhance their transcription. Thus high SOX2 expression, up-regulates the expression of key cell cycle inhibitor genes like RBL2 and CDKN2B and keeps cells in a dormant state. This phenomenon allows colon cancer cells to escape from cytotoxic drug therapy directed at rapidly dividing cells and cause treatment failure and disease relapse.

Stem Cell Transcription Factor SOX2 in Synovial Sarcoma and Other Soft Tissue Tumors

Stem Cell Transcription Factor SOX2 in Synovial Sarcoma and Other Soft Tissue Tumors Book
Author : Hebatalla Zayed
Publisher : Unknown
Release : 2019
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Soft tissue tumors, as an important oncology domain, entail different entities and are challenging regarding diagnosis and therapy. Here, we focused on synovial sarcoma alongside with other soft tissue tumors and specifically analyzed the expression and amplification of the gene SOX2 which has the full name SRY (sex determining region Y)-box2. SOX2 is a transcription factor responsible for the pluripotency of undifferentiated embryonic stem cells, promoting cellular proliferation and promoting invasion, migration and metastases in melanoma and other tumors. We also tested AntiHistone H3-trimethyl K27 (H3K27me3) expression in SOX2 positive cases in an attempt to correlate SOX2 gene expression with the posttranslational protein modification H3K27me3, both of which having been associated with stemness features of cancer cells. In our study, we included all samples (n=60) of synovial sarcoma at the Friedrich-Schiller University hospital of Jena (Germany) between January 2013 and December 2015 in a retrospective observational manner. We excluded cases whose histopathological material was not available anymore in the institute (n=6) and cases (n=4) whose paraffin block was not optimal for further investigation. Clinicopathological and Immunohistochemical analysis were performed by our institutional pathology team according to standard diagnostic protocols e.g. using antibodies against EMA, Bcl2, PanCK, CK7, CD34, Ki67 and S100. Molecular confirmation of the diagnosis was routinely performed by FISH and/or PCR to detect the t(x;18) translocation. We also employed tissue microarrays of different soft tissue tumors to compare the expression in synovial sarcoma with other sarcoma entities. Results were collected, tabulated and statistically analyzed. About 60 % of all synovial sarcoma cases were positive to Sox2. Meanwhile out of 343 soft tissue tumors, varying from nodular fasciitis to undifferentiated pleomorphic sarcoma, only 13 cases (3.8%) were Sox2 positive. Of these, 11 (84.6%) were undifferentiated high grade pleomorphic sarcoma. Out of 35 Sox2 positive synovial sarcoma cases, 25 (71, 4%) were H3K27me3 positive and 10 (28, 6%) were negative. SOX2 amplification was not detectable in 6 randomly chosen synovial sarcoma cases showing SOX2 protein expression. Sox2, a principal stem-cell transcription factor, is evidently involved in the tumorigenesis of many tumor entities. In soft tissue tumors, however, expression is largely restricted to synovial sarcoma. Immunohistochemical detection of SOX2 can thus help in the diagnostic challenge in differentiating synovial sarcoma from other soft tissue tumors. H3K27me3 was also found to be positive in the majority of Sox2-positive synovial sarcomas and this correlates with the idea that these tumors might have a pluripotent cell population as tumor-initiating cells. We think that this finding supports the hypothesis of synovial sarcoma as product of pluripotent mesenchymal stem cell populations rather than being derived from mutations in terminally differentiated cells. The results may add to the diagnostic scheme for synovial sarcoma diagnosis. Moreover, Sox2 might reveal a molecular approach in cancer treatment, namely by targeting epigenetic modulators that seems to play a role in SOX2 gene regulation.

ROLE OF ALDH SOX2 AS TUMOUR

ROLE OF ALDH   SOX2 AS TUMOUR Book
Author : Tung-Yung Chui
Publisher : Open Dissertation Press
Release : 2017-01-26
ISBN : 9781361008539
Language : En, Es, Fr & De

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Book Description :

This dissertation, "The Role of ALDH and SOX2 as Tumour Initiating Cell Markers in Non-small Cell Lung Cancer" by Tung-yung, Chui, 崔董庸, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: The abundance of tumour initiating cells (TIC) has been suggested to be an important prognostic indicator in cancers. Both SOX2 and ALDH have been individually reported to be putative TIC markers but their combined status is unclear and their usefulness in the prognostication of non-small cell lung cancer (NSCLC)has not been reported. This study investigated the patterns of ALDH and SOX2 protein expression in NSCLC using immunohistochemistry. Expression was graded using semi-automated signal capturing and image analysis software. ALDH and SOX2 were expressed in 41% and 43% of all NSCLC, respectively. ALDH was expressed in 36% of adenocarcinomas (AD)and 65% of squamous cell carcinomas (SCC), while SOX2 was expressed in 36% of AD and 80% of SCC., respectively. Taking all cases into consideration, the expression of ALDH and SOX2 significantly correlated with each other (p=0.003). No prognostic value of the abundance of ALDH and SOX2-expressing cancer cells was found with regard to all NSCLC or in AD. In contrast, for SCC, a significantly better prognosis with longer cancer-specific survival (CSS) and disease-free survival was found in tumours with higher ALDH expression, while a longer CSS was found in those with higher SOX2 expression. Contrary to the hypothesis that a high TIC content indicated by high combined ALDH and SOX2 expression would predict poor patient outcome, amongst all NSCLC, the combined phenotype of SOX2+/ALDH-was associated with the worst prognosis compared with the SOX2+/ALDH+(p=0.026) and SOX-/ALDH-(p=0.048), while no significant difference was observed with the SOX-/ALDH+ phenotypes. In view of the tight correlation between ALDH and SOX2 protein levels, in vitro studies were performed to investigate whether ALDH could be an upstream regulator of SOX2 expression. Pharmacological inhibition of ALDH enzyme function led to down-regulation of SOX2 mRNA and nuclear protein expression in lung cancer cell lines, indicating a regulatory role of ALDH on the SOX2 stemness pathway in lung cancer. In summary, the findings implicate complex factors are likely to be involved in determining the expression levels of ALDH and SOX2 in clinical lung cancers and their mechanisms affecting patient survival remain to be clarified. Further investigations on the specificity of ALDH/SOX2 as TIC marker, TIC interaction with the tumour micro-environment, and potential complex antagonistic functions of ALDH in TIC maintenance are required. DOI: 10.5353/th_b5091320 Subjects: Transcription factors Aldehyde dehydrogenase Lungs - Cancer

Stem Cells and Cancer

Stem Cells and Cancer Book
Author : Sadhan Majumder
Publisher : Springer Science & Business Media
Release : 2009-06-07
ISBN : 9780387896113
Language : En, Es, Fr & De

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Book Description :

Cancer is a primary cause of human mortality worldwide. Despite decades of basic and clinical research, the outcome for most cancer patients is still dismal. Some stumbling blocks to developing effective therapy include the heterogeneity of cancer tissues, the lack of knowledge about the critical molecular mechanisms in cancer tissues (which are typically aberrant compared with mechanisms in normal tissue), and the lack of good mechanism-based therapeutic approaches. The recent findings that most cancers contain a small fraction of self-renewing, differentiation-blocked stem cell-like cells (cancer stem cells) and that it is these cells—and not the major bulk of the tissue—that are the root cause for cancer initiation and metastasis have also highlighted the need to change our approach to cancer therapy. The objectives of this book, therefore, would be to impart up-to-date information about the role of stem cells in the development of normal and cancerous tissue, the mechanisms that differentiate normal from cancerous functions, and the use of these findings in developing mechanism-based therapies.

Altered Levels of SOX2 and Its Associated Protein Musashi2 Disrupt Critical Cell Functions in Cancer and Embryonic Stem Cells

Altered Levels of SOX2  and Its Associated Protein Musashi2  Disrupt Critical Cell Functions in Cancer and Embryonic Stem Cells Book
Author : Erin Lynn Wuebben
Publisher : Unknown
Release : 2016
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

The transcription factor SOX2 is widely recognized for its critical roles during mammalian embryogenesis. SOX2 has also been examined in cancer; and it has been implicated in the growth, tumorigenicity, drug resistance, or metastasis of over 20 different cancers, including cancers of the brain and pancreas. Thus, we hypothesized that SOX2 is a major player in cancer and may be a potential therapeutic target; however, the effects of SOX2 on the many facets of human cancer have only begun to be explored. Recently, efforts to understand the mechanisms by which SOX2 mediates its effects have explored SOX2 protein-protein interaction landscapes in a number of cellular systems. Previous studies in our laboratory identified proteins, like the RNA-binding protein Musashi2 (Msi2), which interact with SOX2 in multiple cell types, including embryonic stem cells and brain tumor cells. We hypothesized that proteins that interact with SOX2 in multiple cell types are likely to be necessary for the continued growth and function of these cells. The studies presented in this dissertation demonstrate that ESC require Msi2 to maintain self-renewal and pluripotency; and that MSI2 is also required to support the growth and survival of DAOY, U87, and U118 brain tumor cell lines. This dissertation also examined the roles of SOX2 in pancreatic adenocarcinoma (PDAC). Multiple PDAC cell lines were engineered for either inducible overexpression of SOX2 or inducible knockdown of SOX2. Through in vitro growth and tumorigenicity studies with these inducible PDAC cell lines, we determined that SOX2 functions as a biphasic molecular rheostat in PDAC. Furthermore, we determined that inducible elevation of SOX2 in PDAC cells reduces the growth inhibitory effects of MEK and AKT inhibitors, while the inducible knockdown of SOX2 enhanced growth inhibition in the presence of these inhibitors. Altogether, the work presented in this dissertation extends and strengthens our knowledge of SOX2 and its function as a master regulator in multiple cell types, and provides useful platforms for the continued study of these highly deadly malignancies.

Stem and Progenitor Cells in the Central Nervous System

Stem and Progenitor Cells in the Central Nervous System Book
Author : R.S. Nowakowski
Publisher : Karger Medical and Scientific Publishers
Release : 2004-01
ISBN : 3805578709
Language : En, Es, Fr & De

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Book Description :

This publication focuses on the biology of stem and progenitor cells in the developing and mature central nervous system, their response to trauma and potential uses in therapy. The authors, who are leading experts in the field, address topical questions from both basic and clinical neuroscience perspectives such as: non-invasive imaging of stem cell division; the origins of regional diversity in cell types and cell numbers in the stem cell progeny; factors that regulate generation of neurons and glial cells from stem cells during normal development; the role of genetic and environmental factors in the regulation of stem cell function; the role of stem cells in mediating the effects of brain trauma and its recovery, and the therapeutic uses of stem cells. Offering a unique compilation of articles on the biology and the therapeutic applications of stem cells in the embryonic and mature nervous systems, this volume will be of great value to neuroscientists, developmental biologists, cancer biologists and clinical neurologists.

DDX17 P72 a Sox2 Binding Partner Regulates Sox2 to Sustain Tumorigenic and Stem like Properties in a Phenotypically Distinct Subset of Estrogen Positive Breast Cancer Cells

DDX17  P72   a Sox2 Binding Partner  Regulates Sox2 to Sustain Tumorigenic and Stem like Properties in a Phenotypically Distinct Subset of Estrogen Positive Breast Cancer Cells Book
Author : Hind M. Alqahtani
Publisher : Unknown
Release : 2016
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Sox2, an embryonic stem cell marker, is involved in the pathogenesis of breast cancer (BC). Sox2 expression is associated with a poor clinical outcome in BC patients. Based on the differential Sox2 transcriptional activity, we have identified the two phenotypically distinct cell subsets, namely reporter responsive (RR) and reporter unresponsive (RU) cells. RR cells are more tumorigenic and stem-like than RU cells. The goal of this study is to understand the mechanisms of regulating Sox2 transcriptional activity. By using liquid chromatography-mass spectrometry and co-immunoprecipitation, we found that DDX17 is a Sox2 binding partner in ER+ BC cell lines. The interaction between DDX17 and Sox2 was found to be significantly higher in the RR cell subset than in the RU subset. DDX17 was found to bind to the Sox2 promoter and regulate its expression in RR cells derived from the MCF7 cell line. Although, the protein level of Sox2 was unaffected in RU and RR cell subsets. Upon siRNA knockdown of DDX17, the transcriptional activity of Sox2 was significantly decreased in RR cells but not in RU cells. Correlating with these findings, siRNA knockdown of DDX17 drastically reduced the tumorigenic and stem-like properties in RR cells, as observed by decreased in colony formation and mammosphere formation efficiency. In conclusion, DDX17 regulates Sox2 to maintain tumorigenic and stem-like properties. The interaction between Sox2 and DDX17 provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications.

Sox2 is a Master Regulator of Differentiation in Respiratory Epithelium

Sox2 is a Master Regulator of Differentiation in Respiratory Epithelium Book
Author : David H. Tompkins
Publisher : Unknown
Release : 2011
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

The most frequently amplified locus in human lung squamous cell carcinoma contains the gene for the transcription factor Sox2, yet the role of Sox2 in lung is unknown. The present study was undertaken to investigate the function of Sox2 in perinatal and adult lung. The central findings of this study are (a) Sox2 is necessary and sufficient for differentiation of Clara, ciliated, and goblet cells of the conducting airway epithelium, and (b) Sox2 is a positive regulator of proliferation in conducting airway epithelium. Previous studies have shown that Sox2 is critical for diverse biological processes, including maintenance and pluripotency of embryonic stem cells, morphogenesis of the trachea, esophagus, and eye, and development of differentiated cells in adult tongue, ear, and brain. In developing lung, Sox2 is present exclusively in cells lining the developing tubules (the future bronchioles). In mature lung, Sox2 is present in the epithelium of the conducting airways (bronchioles) and is absent from the epithelium of the gas-exchange compartment (alveoli). In the present study, perinatal knockout of the Sox2 gene specifically in the Clara cells of the mouse conducting airways resulted in an abnormal, low cuboidal epithelium with reduced proliferation and loss of the predominant differentiated conducting airway cell types (Clara and ciliated cells). Further, the Sox2-null bronchiolar epithelium was incapable of forming goblet cells during an allergen-challenge experiment, whereas Sox2-competent bronchiolar epithelium in control animals produced an abundance of goblet cells. Consistent with a role in differentiation, luciferase-reporter assays using immortalized human bronchiolar epithelial cells demonstrated Sox2 activation of the promoter region of differentiation marker genes (Clara cell Scgb1a1, Ciliated cell marker FoxJ1, Goblet cell marker Agr5). Sox2 inhibited a TGF-[beta] signaling assay in vitro and directly bound the TGF-[beta] signalingiiitransducer SMAD3, defining a possible mechanism by which Sox2 contributes to increased proliferation. In vivo, transgenic Sox2 expression was induced in the Clara cells of the bronchiolar epithelium (where endogenous Sox2 was already present), and in the alveolar type II cells of the alveolar epithelium (where endogenous Sox2 was not present). Transgenic Sox2 expression in Clara cells induced a short term increase in proliferation and a loss of the Clara cell marker protein Scgb1a1. Transgenic Sox2 expression in alveolar type II cells led to a short-term increase in proliferation, and was sufficient to induce the dramatic, widespread appearance of abnormal alveolar cell clusters possessing well-formed ectopic cilia and marker proteins characteristic of bronchiolar Clara and ciliated cells. Taken together, these results support the following concepts:- In lung growth, homeostasis and allergen challenge, bronchiolar Clara cells differentiate intoClara, ciliated, and goblet cells in a process that requires Sox2.- Ectopic Sox2 expression in alveolar type II cells is sufficient to induce robust reprogrammingof alveolar epithelium into bronchiolar epithelial-like cells.- Sox2 contributes to the positive regulation of proliferation in conducting airway epithelial cells.

Molecular Regulation of Sox2 Expression During Differentiation of Chick Embryonic Stem Cells

Molecular Regulation of Sox2 Expression During Differentiation of Chick Embryonic Stem Cells Book
Author : A. M. Ghanem
Publisher : Unknown
Release : 2010
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

The transcription factor Sox2 has a key role not only in maintaining stem state but also in specification of neural fate of embryonic cells. Multiple regulatory elements have been identified in the Sox2 locus (Uchikawa et al, 2003). In the developing embryo, these regulatory elements are activated differentially in time and space. We studied the activity of 25 defined regulatory elements of the Sox2 promoter in three different lines of chick ES cells. By transfection of plasmids encoding Enhanced Green Fluorescent Protein (EGFP) and the minimal promoter thymidine kinase (tk) coupled with individual Sox2 regulatory elements we find that the Sox2 enhancer N2 has the highest activity in proliferating chick cell lines compared with other enhancer regions. Under conditions that induce ES cells to differentiate into neurons the activity of the N2 enhancer increased along with an increase in levels of expression of Sox2 mRNA. Further analysis of the N2 enhancer sequence identified two subregions with 176 and 73 base pairs (bp) which are highly conserved between chick, mouse and man. Functional studies performed with the tk-EGFP reporter plasmids under the control of five regulatory sequences containing the mouse N2 enhancer in its full length, its two sub-regions (176 and 73 bp) or sequences composed of the full length of the mouse N2 from which each of the two sub-regions 176 bp and 73 bp has been deleted confirmed that the two sub-regions of the N2 enhancer account for its activity in both proliferating cES cells as well as their induced neural differentiation state. These findings suggest that N2 core regulatory regions encode conserved instructions required to direct expression of Sox2 both in embryonic stem cells induced to neural differentiation and in the neural plate of the embryo itself.

Tissue Specific Transcriptional Regulation of Sox2

Tissue Specific Transcriptional Regulation of Sox2 Book
Author : Yiu-Fai Angus Lee,李耀輝
Publisher : Unknown
Release : 2017-01-27
ISBN : 9781361421833
Language : En, Es, Fr & De

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This dissertation, "Tissue-specific Transcriptional Regulation of Sox2" by Yiu-fai, Angus, Lee, 李耀輝, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Tissue-specific transcriptional regulation of Sox2 Submitted by Angus, Yiu Fai, Lee for the Degree of Doctor of Philosophy at the University of Hong Kong in April 2007 Sox2 is a member of the Sox (SRY-type HMG box) gene family that encode transcription factors with a single high mobility group (HMG) DNA binding domain. Sox2 is located on chromosome 3 and it belongs to the SOX B1 subgroup, which also contains Sox1 and Sox3. During embryonic development, Sox2 is found to be expressed in a wide variety of tissues such as neural tissues of central nervous system, gut and lens epithelium. Recently, Sox2 is demonstrated to be required for the development of all the sensory regions in the inner ear. Also, the regulation of Sox2 expression in tissue specific manner is known to be under the control of multiple regulatory elements. Two alleic mouse mutants, light coat and circling (Lcc) and yellow submarine (Ysb), display recessive circling behavior and deafness with a semi-dominant yellow coat color. Lcc was made by X-ray irradiation mediated DNA inversion, while Ysb was generated by the random insertions of a transgene (pAA2), and both Lcc and Ysb mutation are localized on chromosome 3. Sox2 coding region is remaining intact in Lcc and Ysb, but the Sox2 expression was dramatically down-regulated in the otocyst even though it appeared normal in other tissues, suggesting that tissue specific loss of Sox2 does lead to the defect in the inner ear. This may be explained by the disruption of one or more tissue specific element that drives expression of Sox2 in the inner ear. Therefore, the first aim iof this study is to identify the regulatory elements that direct Sox2 expression in the inner ear by a combination of bioinformatics, comparative genomic analyses and transgenic approaches. Bioinformatics have been used to compare long genomic DNA sequences between species to reveal conserved non-coding sequences (CNS), which are useful for identifying candidate regulatory regions of genes. Some CNS were examined for Sox2 specific regulatory elements by transgenic approach. Transgenic mice were generated using bacterial artificial chromosome (BAC) DNA, which covers the Sox2 coding region and large areas of upstream and downstream sequence to ensure the inclusion of the endogenous promoter and most if not all of the regulatory elements for Sox2. Also, the Lcc breakpoints were determined in order to help us identify the inner ear specific Sox2 regulatory element. These studies suggested that the inner ear specific Sox2 regulatory elements do not residue within 185 kb downstream of Sox2, and they may act from a long-range distance to regulate Sox2 in inner ear specific manner. Previous work had indicated that Sox2 is likely to be acting upstream of Math1 during development of the sensory progenitors in the inner ear. The second aim of this study is to determine whether Sox2 directly or indirectly regulates Math1 expression. To address +/βgal this aim, a transgenic construct was pronuclear microinjected into the Math1 oocytes, where Sox2 was ectopically expressed under the control of Hoxb2 enhancer element. These double transgenic embryos demonstrated that Sox2 can transactivate Math1 in vivo but Math1 transactivation was not found in all ectopic Sox2 expression sites.

Genetic Analyses of the Roles of Sox2 and Sox18 in Mouse Hair Development and Growth

Genetic Analyses of the Roles of Sox2 and Sox18 in Mouse Hair Development and Growth Book
Author : Siu-Yin Bryan Ho,何兆賢
Publisher : Open Dissertation Press
Release : 2017-01-27
ISBN : 9781361357590
Language : En, Es, Fr & De

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This dissertation, "Genetic Analyses of the Roles of Sox2 and Sox18 in Mouse Hair Development and Growth" by Siu-yin, Bryan, Ho, 何兆賢, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: The mouse pelage hair consists of three types of hair coined primary (guard), secondary (awls and auchenes) and tertiary (zigzag) hair. They display distinct morphologies and are induced consecutively during hair morphogenesis. Previously two identified regulatory mouse mutants, Yellow submarine (Ysb) and Light coat and circling (Lcc) which the chromosomal rearrangements have disrupted the cis-acting regulatory elements of Sox2; resulting in the loss of Sox2 expression in the inner ear. The mutants displayed lighter hair coat color due to a reduction in the proportion of secondary hair and increased proportion of tertiary hair. Sox18 null mutants display darker coat colour and reduced proportion of zigzag hair. To dissect the underlying mechanisms of the phenotypes in hair type specification in 〖Sox2〗 DEGREESYsb and 〖Sox2 〗 DEGREESLcc mutants and the role of Sox2 and Sox18 in regulating the process; the expression of Sox2 in the hair follicle and the change in the density of hair types in mutants were analyzed. I have identified the expression pattern of Sox2 in the dermal papilla (DP) of the hair follicle and verified its down-regulation in 〖Sox2〗 DEGREESYsband 〖Sox2 〗 DEGREESLcc mutants. The DP at the base of hair follicle is the signaling center for the regulation of hair development. Sox2 is specifically expressed in the DP of primary and secondary but not in tertiary hair while Sox18 is expressed in the DP of all hair types. Analysis of Sox2 mutants showed that the number of secondary hair was normal at induction but was reduced and accompanied by an increase in tertiary hair in adult mice. The number of tertiary hair was reduced in Sox18 null mutants. To gain insight into the molecular basis of hair type specification and potential targets of Sox2 in the regulation, gene expression profile in DP cells of 〖Sox2 〗 DEGREES(EGFP/+)and 〖Sox2 〗 DEGREES(EGFP/Ysb) mice was examined; the data suggests that genes in the Wnt and BMP signalling pathway were down-regulated in Sox2 mutants; while Runx3 and Corin may act downstream of Sox2 in regulating hair type specification and pigmentation. Hair follicles enter cycles of growth and regression throughout life during the hair cycle. Sox2 was only expressed in the growth phase while Sox18 was persistently expressed throughout the hair cycle. I further asked if Sox2 and Sox18 regulate post-natal hair development by analysing the expression pattern of Sox2 and Sox18 in wildtype mice and mutants throughout the hair cycle and the progression of hair growth in the mutants. The growth phase of the first hair cycle was extended in Sox2 mutants while the hair cycle in Sox18 null mutants was normal. Cell proliferation was compromised during hair regeneration leading to a delay in hair regeneration in Sox2 mutants. Sox2 and Sox18 showed overlapping expression in the DP and both regulate hair type specification. To test if Sox2 and Sox18 synergistically regulate hair development, the 〖Sox2〗 DEGREES(Ysb/Ysb);〖Sox18〗 DEGREES(-/-) mutants have been generated. Hair morphogenesis and differentiation were impaired; while the number of tertiary hair was increased with reduced number of secondary hair, which phenocopied that of Sox2 mutants. In conclusion, the results suggest that Sox2 and Sox18 functions synergistically on the regulation of hair growth and differentiation. DOI: 10.5353/th_b5328054 Subjects: Hair

The Role of SOX2 in Regulation of Pluripotency and Early Cell Fate Decision in Embryos and Embryonic Stem Cells

The Role of SOX2 in Regulation of Pluripotency and Early Cell Fate Decision in Embryos and Embryonic Stem Cells Book
Author : Maria Keramari
Publisher : Unknown
Release : 2008
ISBN : 0987650XXX
Language : En, Es, Fr & De

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The transcription factor Sox2 (SRY-related HMG box gene 2) plays a pivotal role in maintaining self-renewal and pluripotency in embryonic stem (ES) cells derived from the inner cell mass (ICM) of the embryo Previously it was shown that Sox2-/- mouse embryos die soon after implantation, ' how materna! Sox2" transcripts may mask an eariier phenotype. This study has shown that siRNA knock-down of Sox2 at the 2-cell stage of the preimplantation mouse embryo results in embryo arrest at the morula stage, increased cellular apoptosis and loss of ability to generate the first differentiated tissue in the embryo, the trophectoderm (TE).

The Role of SOX2 in Colon Cancer Progression

The Role of SOX2 in Colon Cancer Progression Book
Author : Debasish Boral
Publisher : Unknown
Release : 2014
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

SRY (sex determining region Y)-box 2 (SOX2) is one the embryonic stem cell transcription factors that is capable of reprogramming adult differentiated cells into an induced pluripotent cell. SOX2 is amplified in various types of epithelial cancers and its high its expression correlates with poor prognosis and decreased patient survival. Aberrant Wnt signaling drives the colo-rectal carcinogenic process and is a major determinant of the disease outcome. This study demonstrates that SOX2 counteracts Wnt driven tumor cell proliferation and maintains quiescence in a sub-population of Colo-Rectal Cancer (CRC) cells. High SOX2 expression is found in a sub-group of CRC patients with advanced disease. High SOX2 expression coupled with low Wnt activity was found in SW620 metastatic CRC cell line, while the opposite was true for the isogenic SW480 primary tumor cell line. SOX2 silencing increased Wnt activity and enhanced the oncogenic potential of SW620 cells in vitro and in vivo while over-expression had opposite effects in SW480 cells. SOX2 up-regulates the expression of PTPRK and PHLPP2 protein phosphatase genes which in turn attenuates Wnt activity by interfering with Protein Kinase A, B and C mediated beta catenin phosphorylation at Serine 552 and 675 amino acid residues thereby diminishing its nuclear sequestration and transcriptional activation. Thus SOX2 mitigates growth factor mediated Wnt activation in CRC cells and inhibits cellular proliferation so that these cells are forced to change their oncogene addiction. In effect, high SOX2 expression causes clonal evolution of APC mutant CRC cells from a state of high Wnt dependency to a state of low Wnt dependency in the process making such cells resistant to Wnt inhibitor therapy. Enhanced SOX2 transcriptional activity was associated with increased proportion of cancer cells in G0 -G1 phase of cell cycle. Changing SOX2 protein levels in cells had a direct correlation with mRNA levels of RBL2-HUMAN and CDKN2B genes, which serve as regulators of G0 and G1 respectively. SOX2 was shown to physically bind and to the promoter region of these two genes and enhance their transcription. Thus high SOX2 expression, up-regulates the expression of key cell cycle inhibitor genes like RBL2 and CDKN2B and keeps cells in a dormant state. This phenomenon allows colon cancer cells to escape from cytotoxic drug therapy directed at rapidly dividing cells and cause treatment failure and disease relapse.

The Roles of Sox2 and Sox18 in Hair Type Specification and Pigmentation

The Roles of Sox2 and Sox18 in Hair Type Specification and Pigmentation Book
Author : N S Michelle Chan,陳雁璇
Publisher : Open Dissertation Press
Release : 2017-01-27
ISBN : 9781361421970
Language : En, Es, Fr & De

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Book Description :

This dissertation, "The Roles of Sox2 and Sox18 in Hair Type Specification and Pigmentation" by N S, Michelle, Chan, 陳雁璇, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Michelle Chan MPhil. Thesis 2007 Abstract of thesis entitled The Roles of Sox2 and Sox18 in Hair Type Specification and Pigmentation Submitted by Michelle, N.S. Chan for the Degree of Master of Philosophy at the University of Hong Kong in June 2007 Guards, awls, auchenes and zigzags are the four main murine hair types. Except guards, the rest are agouti hairs with a yellow band. Hair pigmentation is controlled through the interactions between Agouti Signaling Protein (ASP)/alpha-Melanocortin Stimulating Hormone (α-MSH) and the Melanocortin-1 Receptor (MC-1R) located on the melanocytes. In contrast to hair pigmentation, little is known about how the different hair types are specified. Although the Edar and BMP pathways have been shown to regulate the specification of guard/zigzag and awl hairs respectively, the underlying mechanisms are poorly understood. Hair follicle (HF) induction destines the future follicular patterning, the interactions between Wnt and Dkk through a reaction-diffusion mechanism control HF spacing. The Notch signaling pathway is required for cell fate determination and patterning in many organisms such as Drosophila, chick and 1Michelle Chan MPhil. Thesis 2007 mice. Although Notch receptors and their ligands are expressed in both developing and adult HFs, their roles in HF patterning are still largely unknown. Light Coat and Circling (Lcc) and Yellow Submarine (Ysb), are allelic mouse mutants which display recessive deafness and a semi-dominant coat color change from agouti to yellow as a result of loss of black awls, increase in zigzags and alteration of pigmentation pattern in hairs such as an extra yellow band appeared in Lcc. In Lcc and Ysb chromosomal rearrangements result in loss of cis-regulatory sequences controlling Sox2 gene expression in the inner ear. In Lcc, SOX2 expression is reduced in the pituitary, the α-MSH production site. Sox18 null mice look darker than wild-type and display a reduced proportion of zigzag and increased awl hairs, these suggesting a role for Sox18 in regulating hair type specification and pigmentation. These three hair type specific mouse mutants are hence valuable tools to study the roles of Sox2 and Sox18 in hair type specification and pigmentation. I have aimed to understand the roles of Sox2 and Sox18 in regulating hair type specification and pigmentation by investigating the mechanism underlying the Ysb Lcc hair phenotypes in Sox2 and Sox2 mice. I found that Sox2 and Sox18 are expressed in HFs throughout development. Altered or loss of SOX2 and SOX18 Ysb/Ysb Lcc/Lcc -/- expression was found in Sox2 /Sox2 and Sox18 respectively. To test for genetic/epistatic interactions between Sox2 and Sox18 in hair type Ysb specification and pigmentation, we generated Sox2;Sox18 compound mutants. Interestingly, compound homozygous are yellow with absence of guard, awl, and auchene hairs. These results reveal that Sox2 and Sox18 are not only important for hair type specification, but also regulate yellow and black pigments formation. 2Michelle Chan MPhil. Thesis 2007 Ysb/Ysb Lcc/Lcc In Sox2 and Sox2, induction of more HFs leads to alterations in hair Lcc/Lcc frequency. Results showed that Notch1 is down-regulated in HFs of Sox2 mutants. In mouse neocortex development, Sox2 has been shown to positively regulate Notch1. The interactions between Sox2 and Notch1 in HF spacing were demonstrated and a new

Oct3 and Sox2 Expression in Mammary Carcinoma Cells

Oct3 and Sox2 Expression in Mammary Carcinoma Cells Book
Author : Yvette Marie Soignier
Publisher : Unknown
Release : 2010
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

A complex transcriptional circuitry is essential in maintaining the self-renewal capacity and the undifferentiated state of embryonic stem cells (ESCs). Key factors in this pluripotency network include Sox2, Nanog, and Oct3/4, which form multiple positive and negative feedback loops to regulate an array of downstream genes. Although it was previously thought that pluripotency factors are downregulated upon differentiation, the phenotypic similarities between ESCs and cancer cells have led to speculation that common underlying regulatory mechanisms may exist. For example, the cancer phenotype includes a block in differentiation, limitless replicative potential and increased proliferation, characteristics that are also observed in pluripotent embryonic stem cells. Taken together, these observations regarding similarities in tumor cells and embryonic stem cells suggest regulatory mechanisms that may be shared in development and cancer. In the studies presented here, I investigated the expression, localization, and function of Nanog, Sox2, Oct4 and particularly the Oct3 splice variant protein in cancer. I performed a variety of biochemical, genetic and pharmacological experiments to elucidate potential roles of these pluripotency factors in maintaining the cancer phenotype, using a panel of breast cancer cells as a model system. Expression of Sox2 and the Oct3 isoform was detected in all breast cancer cell lines investigated, whereas Nanog and Oct4 expression were not detected. Moreover, Sox2 was localized to both the cytoplasm and nucleus, but Oct3 expression was detected exclusively the cytoplasm of breast cancer cells. This study also shows that Oct3 and Sox2 are upregulated in a number of breast cancer cell lines when compared to expression levels in mammary epithelial cells. I also determined that Src is an upstream regulator of Oct3 and Sox2 expression. Given the known function of Sox2 as a regulator of the cell cycle, I focused subsequent studies on the characterization and function of Oct3. Results showed that the Oct3 N-terminal domain contains an auto-inhibitory sequence that blocks its nuclear translocation despite the presence of a functional nuclear localization signal. Additional experiments to investigate Oct3 function suggested that Oct3 may be involved in regulating the cell cycle and that this regulation may be in concert with Sox2 and [beta]-catenin to modulate cyclin D1 expression. However, studies of Oct3 function in cancer remain inconclusive due to technical difficulties in Oct3 RNAi that precluded achieving consistent Oct3 knockdown. Despite these difficulties, the data presented here suggest that Oct3 may play a role in maintaining the cancer phenotype, warranting further functional studies.