The Sox Family of Transcription Factors: Versatile Regulators of Stem and Progenitor Cell Fate

Howard Hughes Medical Institute at Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, 185 Cambridge Street, Boston, MA 02114, USA
Cell stem cell (Impact Factor: 22.27). 01/2013; 12(1):15-30. DOI: 10.1016/j.stem.2012.12.007
Source: PubMed


Sox family transcription factors are well-established regulators of cell fate decisions during development. Accumulating evidence documents that they play additional roles in adult tissue homeostasis and regeneration. Remarkably, forced expression of Sox factors, in combination with other synergistic factors, reprograms differentiated cells into somatic or pluripotent stem cells. Dysregulation of Sox factors has been further implicated in diseases including cancer. Here, we review molecular and functional evidence linking Sox proteins with stem cell biology, cellular reprogramming, and disease with an emphasis on Sox2.

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    • "In particular , SOX2 is involved in the regulation of stem cell destination during embryonic development and its expression level is tightly regulated to ensure normal embryonic development [9]. SOX2 depletion by RNA interference promotes embryonic stem cell differentiation into multiple cell types [10]. SOX2 is a key factor capable of inducing pluripotency in somatic cells along with KLF4, Oct3/4, and c-Myc. "
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    ABSTRACT: Expression of SOX-2 and Oct4 as markers for the identification of cancer stem cells (CSCs) has been revealed in several malignancies. In this study, the co-expression of SOX-2 and Oct4 and their correlation with clinicopathological features of endometrial adenocarcinomas (EACs) was investigated. SOX-2 and Oct4 expression was assessed by immunohistochemistry in 27 (39.13%) stage IA and in 42 (60.87%) stage IB International Federation of Gynaecology and Obstetrics (FIGO) EACs and related to the clinicopathological features of patients. The expression of SOX-2 was confirmed in 62/69 tumour specimens compared to Oct4 expression in 46/69 specimens (P = 0.015) and no difference in median staining intensity between SOX-2 and Oct-4 was observed. The highest median SOX-2 expression was found in high-grade (G3) EAC samples compared to moderate-grade (G2) EAC specimens (P = 0.020) and low-grade (G1) specimens (P = 0.008), while no differences in median Oct4 expression in EAC samples according to grading were present. In G3 specimens, significantly higher median SOX-2 expression was noted compared to Oct4 (P = 0.002). SOX-2 and Oct4 co-expression was observed only in G1 EAC (R: 0.51; P = 0.031). Age of EAC diagnosis was positively correlated with SOX-2 expression (b = 0.193; R(2) = 10.83%; P = 0.003) but not to age of menarche, menopause, parity or body mass index. There is no need to use SOX-2 expression as a poor outcome predictor in stage I EAC, and SOX-2 expression should be analysed in more advanced stages.
    International journal of clinical and experimental pathology 09/2015; 8(7):8189-98. · 1.89 Impact Factor
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    • "Accordingly, some genes often associated with cancer, such as Myc (Nakagawa et al., 2008; Wernig et al., 2008), p53 (Krizhanovsky and Lowe, 2009), and telomerase (Batista et al., 2011; Park et al., 2008), have been implicated in cellular reprogramming. Additionally, two reprogramming factors, Oct4 and Sox2, can be oncogenic in some cellular contexts (Hochedlinger et al., 2005; Lu et al., 2010; Rudin et al., 2012; Sarkar and Hochedlinger, 2013). Given previous observations that Rb could be involved in cellular dedifferentiation (Calo et al., 2010; McEvoy et al., 2011) and given the similarities between reprogramming and some aspects of tumorigenesis, we set out to identify mechanisms by which Rb suppresses dedifferentiation using iPSC reprogramming as a cellular system. "
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    ABSTRACT: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
    Cell Stem Cell 01/2015; 16(1). DOI:10.1016/j.stem.2014.10.019 · 22.27 Impact Factor
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    • "They share a high degree of amino acid identities, both within and outside the HMG domain, and exhibit extensive functional redundancy (Miyagi et al., 2009). Analyses conducted both in the developing and adult CNS demonstrate that SoxB1 protein function is both sufficient and a prerequisite to maintaining cells in a mitotically active precursor state (Sarkar and Hochedlinger, 2013). Despite this fact, overexpression or misexpression of SoxB1 proteins in immortalized cells in vitro has actually been shown to reduce their proliferation rate (Cox et al., 2012; Otsubo et al., 2008), while removal of one of the SoxB1 genes, Sox2, causes quiescent Muller-glia progenitors in the adult mouse retina to become mitotically active (Surzenko et al., 2013). "
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    ABSTRACT: Organ formation and maintenance depends on slowly self-renewing stem cells that supply an intermediate population of rapidly dividing progenitors, but how this proliferative hierarchy is regulated is unknown. By performing genome-wide single-cell and functional analyses in the cortex, we demonstrate that reduced Sox2 expression is a key regulatory signature of the transition between stem cells and rapidly dividing progenitors. In stem cells, Sox2 is expressed at high levels, which enables its repression of proproliferative genes, of which Cyclin D1 is the most potent target. Sox2 confers this function through binding to low-affinity motifs, which facilitate the recruitment of Gro/Tle corepressors in synergy with Tcf/Lef proteins. Upon differentiation, proneural factors reduce Sox2 expression, which derepresses Cyclin D1 and promotes proliferation. Our results show how concentration-dependent Sox2 occupancy of DNA motifs of varying affinities translates into recruitment of repressive complexes, which regulate the proliferative dynamics of neural stem and progenitor cells. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 12/2014; 9(5). DOI:10.1016/j.celrep.2014.11.013 · 8.36 Impact Factor
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