Overexpression of Transcription Factor Sp1 Leads to Gene Expression Perturbations and Cell Cycle Inhibition
Emmanuelle Deniaud,Joël Baguet,Roxane Chalard,Roxane Chalard,Bariza Blanquier,Lilia Brinza,Julien Meunier,Julien Meunier,Marie-Cécile Michallet,Aurélie Laugraud,Claudette Ah-Soon,Anne Wierinckx,Marc Castellazzi,Joël Lachuer,Christian Gautier,Jacqueline Marvel,Yann Leverrier +16 more
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TLDR
It is shown that the binding to DNA of overexpressed Sp1 induces an inhibition of cell cycle progression that precedes apoptosis and a transcriptional response targeting genes containing Sp1 binding sites in their promoter or not suggesting both direct Sp1-driven transcription and indirect mechanisms.Abstract:
BACKGROUND: The ubiquitous transcription factor Sp1 regulates the expression of a vast number of genes involved in many cellular functions ranging from differentiation to proliferation and apoptosis. Sp1 expression levels show a dramatic increase during transformation and this could play a critical role for tumour development or maintenance. Although Sp1 deregulation might be beneficial for tumour cells, its overexpression induces apoptosis of untransformed cells. Here we further characterised the functional and transcriptional responses of untransformed cells following Sp1 overexpression. METHODOLOGY AND PRINCIPAL FINDINGS: We made use of wild-type and DNA-binding-deficient Sp1 to demonstrate that the induction of apoptosis by Sp1 is dependent on its capacity to bind DNA. Genome-wide expression profiling identified genes involved in cancer, cell death and cell cycle as being enriched among differentially expressed genes following Sp1 overexpression. In silico search to determine the presence of Sp1 binding sites in the promoter region of modulated genes was conducted. Genes that contained Sp1 binding sites in their promoters were enriched among down-regulated genes. The endogenous sp1 gene is one of the most down-regulated suggesting a negative feedback loop induced by overexpressed Sp1. In contrast, genes containing Sp1 binding sites in their promoters were not enriched among up-regulated genes. These results suggest that the transcriptional response involves both direct Sp1-driven transcription and indirect mechanisms. Finally, we show that Sp1 overexpression led to a modified expression of G1/S transition regulatory genes such as the down-regulation of cyclin D2 and the up-regulation of cyclin G2 and cdkn2c/p18 expression. The biological significance of these modifications was confirmed by showing that the cells accumulated in the G1 phase of the cell cycle before the onset of apoptosis. CONCLUSION: This study shows that the binding to DNA of overexpressed Sp1 induces an inhibition of cell cycle progression that precedes apoptosis and a transcriptional response targeting genes containing Sp1 binding sites in their promoter or not suggesting both direct Sp1-driven transcription and indirect mechanisms.read more
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Overexpression of the Transcription Factor Sp1 Activates the OAS-RNAse L-RIG-I Pathway
Valéryane Dupuis-Maurin,Lilia Brinza,Joël Baguet,Emilie Plantamura,Stéphane Schicklin,Solène Chambion,Claire Macari,Martine Tomkowiak,Emmanuelle Deniaud,Yann Leverrier,Jacqueline Marvel,Marie-Cécile Michallet +11 more
TL;DR: The results showed that increased Sp1 level in untransformed cells constitutes a novel danger signal sensed by the OAS-RNase L axis leading to the activation of the RIG-I pathway, and suggested that the Oas- RNase L-RIG- I pathway may be activated in sterile condition in absence of pathogen.
Journal ArticleDOI
Transcriptomic fingerprints in human peripheral blood mononuclear cells indicative of genotoxic and non-genotoxic carcinogenic exposure.
Kevin Hochstenbach,D.M. van Leeuwen,Ralph W.H. Gottschalk,Hans Gmuender,Solvor B. Stølevik,Unni Cecilie Nygaard,Martinus Løvik,Martinus Løvik,Berit Granum,Ellen Namork,H. van Loveren,H. van Loveren,J.H.M. van Delft +12 more
TL;DR: This research identified novel genomics-based candidate markers for genotoxic and non-genotoxic carcinogen exposure in human peripheral blood cells (PBMC) using whole genome microarrays and revealed distinctive transcription factors for both classes.
Journal ArticleDOI
The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75(NTR)-dependent apoptosis.
Grazia Pula,Alessandra Pistilli,Claudia Montagnoli,Anna Maria Stabile,Maria Grazia Rambotti,Mario Rende +5 more
TL;DR: Novel evidence is provided that HTB114 uterine leiomyosarcoma cells are highly sensitive to amitriptyline, supporting the role of p75NTR-dependent apoptosis as a novel cytotoxic mechanism of this drug and of p 75NTR as an inducible stress receptor and a novel target in clinical oncology.
Journal ArticleDOI
DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1.
TL;DR: In this article, the authors demonstrate that the transcription factor Sp1 localizes to DSBs in G1 and is necessary for recruitment of the NHEJ repair factor, 53BP1.
Journal ArticleDOI
Pneumolysin-induced autophagy contributes to inhibition of osteoblast differentiation through downregulation of Sp1 in human osteosarcoma cells
TL;DR: It is suggested that PLY inhibits osteoblast differentiation by downregulation of Sp1 accompanied by induction of autophagy through ROS-mediated regulation of the AMPK/mTOR pathway.
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