A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification

Gilmour, Jane; Assi, Salam A.; Jaegle, U.E.; Kulu, Divine; Werken, Harmen J.G. van de; Clarke, Deborah; Westhead, David R.; Philipsen, Sjaak; Bonifer, Constanze

doi:10.1242/dev.106054

Cited by 59 publications

(73 citation statements)

References 42 publications

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“…Estimates suggest that there are at least 12 000 Sp binding sites within the human genome, and most studies support the idea that Sp1 not only maintains basal transcription, but also contributes to the regulation, i.e. induction and inhibition, of transcription of a large number of cellular genes . The activities of Sp1 are regulated throughout the cell cycle, and are modulated by post‐translational modification(s) in response to a large array of signals as discussed here.…”

Section: Introductionsupporting

confidence: 61%

Sp1 and the ‘hallmarks of cancer’

2015

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For many years, transcription factor Sp1 was viewed as a basal transcription factor and relegated to a role in the regulation of so-called housekeeping genes. Identification of Sp1's role in recruiting the general transcription machinery in the absence of a TATA box increased its importance in gene regulation, particularly in light of recent estimates that the majority of mammalian genes lack a TATA box. In this review, we briefly consider the history of Sp1, the founding member of the Sp family of transcription factors. We review the evidence suggesting that Sp1 is highly regulated by post-translational modifications that positively and negatively affect the activity of Sp1 on a wide array of genes. Sp1 is over-expressed in many cancers and is associated with poor prognosis. Targeting Sp1 in cancer treatment has been suggested; however, our review of the literature on the role of Sp1 in the regulation of genes that contribute to the 'hallmarks of cancer' illustrates the extreme complexity of Sp1 functions. Sp1 both activates and suppresses the expression of a number of essential oncogenes and tumor suppressors, as well as genes involved in essential cellular functions, including proliferation, differentiation, the DNA damage response, apoptosis, senescence and angiogenesis. Sp1 is also implicated in inflammation and genomic instability, as well as epigenetic silencing. Given the apparently opposing effects of Sp1, a more complete understanding of the function of Sp1 in cancer is required to validate its potential as a therapeutic target.

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Section: Introductionsupporting

confidence: 61%

Sp1 and the ‘hallmarks of cancer’

2015

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“…A2lox ESCs [a gift from Michael Kyba (Kyba et al, 2002)] or Bry-GFP ESCs were cultured and transfected as described previously (Gilmour et al, 2014; Lichtinger et al, 2012; Regha et al, 2015). ESCs were differentiated as described previously (Gilmour et al, 2014; Lancrin et al, 2010; Lichtinger et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…ESCs were differentiated as described previously (Gilmour et al, 2014; Lancrin et al, 2010; Lichtinger et al, 2012). Further details can be found in the .…”

Section: Methodsmentioning

confidence: 99%

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Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

et al. 2016

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The transmission of extracellular signals into the nucleus involves inducible transcription factors, but how different signalling pathways act in a cell type-specific fashion is poorly understood. Here, we studied the regulatory role of the AP-1 transcription factor family in blood development using embryonic stem cell differentiation coupled with genome-wide transcription factor binding and gene expression analyses. AP-1 factors respond to MAP kinase signalling and comprise dimers of FOS, ATF and JUN proteins. To examine genes regulated by AP-1 and to examine how it interacts with other inducible transcription factors, we abrogated its global DNA-binding activity using a dominant-negative FOS peptide. We show that FOS and JUN bind to and activate a specific set of vascular genes and that AP-1 inhibition shifts the balance between smooth muscle and hematopoietic differentiation towards blood. Furthermore, AP-1 is required for de novo binding of TEAD4, a transcription factor connected to Hippo signalling. Our bottom-up approach demonstrates that AP-1- and TEAD4-associated cis-regulatory elements form hubs for multiple signalling-responsive transcription factors and define the cistrome that regulates vascular and hematopoietic development by extrinsic signals.

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“…Housekeeping genes primarily use TATA-less, GC-rich promoters (Zhu et al, 2008) and transcriptional activation of such genes in reporter gene assays was found to be mediated mainly by proximal promoter regions containing multiple Sp1 consensus binding sites (Hayashi et al, 1998; Liedtke et al, 2003; Singh et al, 2012; Yamabe et al, 1998). To date, it is clear that Sp1 also contributes to the cell type specific transcriptional regulation of genes involved in differentiation and developmental processes (Gilmour et al, 2014; Morris and Taylor-Papadimitriou, 2001; Opitz and Rustgi, 2000). Moreover, Sp1 was found to be overexpressed in many cancers, which is positively correlated with progression of the disease (Chiefari et al, 2002; Guan et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control analyses of the Xiphophorus melanoma oncogene

Regneri

Volff

Schartl

2015

Comparative Biochemistry and Physiology Part C: Toxicology &

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Melanoma development in interspecific hybrids of Xiphophorus is induced by the overexpression of the mutationally activated receptor tyrosine kinase Xmrk in pigment cells. Based on the melanocyte specificity of the transcriptional upregulation, a pigment cell specific promoter region was postulated for xmrk, the activity of which is controlled in healthy purebred fish by the molecularly still unidentified regulator locus R. However, as yet the xmrk promoter region is still poorly characterized. In order to contribute to a better understanding of xmrk expression regulation, we performed a functional analysis of the entire putative gene regulatory region of the oncogene using conventional plasmid based reporter systems as well as a newly established method employing BAC derived luciferase reporter constructs in melanoma and non-melanoma cell lines. Using the melanocyte specific mitfa promoter as control, we could demonstrate that our in vitro system is able to reliably monitor regulation of transcription through cell type specific regulatory sequences. We found that sequences within 200 kb flanking the xmrk oncogene do not lead to any specific transcriptional activation in melanoma compared to control cells. Hence, xmrk reporter constructs fail to faithfully reproduce the endogenous transcriptional regulation of the oncogene. Our data therefore strongly indicate that the melanocyte specific transcription of xmrk is not the consequence of pigment cell specific cis-regulatory elements in the promoter region. This hints at additional regulatory mechanisms involved in transcriptional control of the oncogene, thereby suggesting a key role for epigenetic mechanisms in oncogenic xmrk overexpression and thereby in tumor development in Xiphophorus.

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A crucial role for the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification

Cited by 59 publications

References 42 publications

Sp1 and the ‘hallmarks of cancer’

Sp1 and the ‘hallmarks of cancer’

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

Transcriptional control analyses of the Xiphophorus melanoma oncogene

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