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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Apoptotic effect of methanol extract of Picrasma quassioides by regulating specificity protein 1 in human cervical cancer cells.
TL;DR: The results showed that MEPQ decreased the viability and induced caspase‐dependent apoptosis in HEp‐2 cells, and MEPQ reduced Sp1 protein through proteasome‐dependent protein degradation, but not the inhibition of protein synthesis.
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Sp1-mediated ectopic expression of T-cell lymphoma invasion and metastasis 2 in hepatocellular carcinoma.
TL;DR: Evidence is provided illustrating that Sp1 binds directly to the GC box located in the TIAM2S core promoter and that Sp 1‐mediated transcriptional activation is essential for TIam2S ectopic expression in liver cancer cells.
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Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
Patricia Dauer,Vineet Gupta,Olivia McGinn,Alice Nomura,Alice Nomura,Nikita S. Sharma,Nivedita Arora,Bhuwan Giri,Vikas Dudeja,Ashok K. Saluja,Ashok K. Saluja,Sulagna Banerjee +11 more
TL;DR: This study shows that downregulating specificity protein 1 (Sp1), a transcription factor that is overexpressed in pancreatic cancer, activates UPR and results in chronic ER stress, and inhibition of Sp1 leads to lysosomal membrane permeabilization (LMP), a sustained accumulation of cytosolic calcium, and eventually cell death in pancreating cancer.
Journal ArticleDOI
The Zinc-Schiff Base-Novicidin Complex as a Potential Prostate Cancer Therapy
Vedran Milosavljevic,Yazan Haddad,Miguel Angel Merlos Rodrigo,Miguel Angel Merlos Rodrigo,Amitava Moulick,Hana Polanska,David Hynek,David Hynek,Zbynek Heger,Zbynek Heger,Pavel Kopel,Pavel Kopel,Vojtech Adam,Vojtech Adam +13 more
TL;DR: The use of the membrane-penetrating peptide Novicidin connected to zinc-Schiff base as a carrier vehicle for the delivery of zinc to prostate cells and the results strongly suggest that the zinc- Schiff base-Novicidin complex has great potential as a novel anticancer drug.
Journal ArticleDOI
Oncogenic STRAP functions as a novel negative regulator of E-cadherin and p21Cip1 by modulating the transcription factor Sp1
Lin Jin,Pran K. Datta +1 more
TL;DR: A novel mechanism of regulation of E-cadherin and p21Cip1 by STRAP is suggested by modulating Sp1-dependent transcription, and higher expression of STRAP in lung cancer may contribute to downregulation of E and p 21Cip 1 and to tumor progression.
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