title: Overexpression of transcription factor Sp1 leads to gene expression perturbations and cell cycle inhibition.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Inserm, U851, Lyon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Deniaud
authors.forename: Joël
authors.initials: J
authors.lastname: Baguet
authors.forename: Roxane
authors.initials: R
authors.lastname: Chalard
authors.forename: Bariza
authors.initials: B
authors.lastname: Blanquier
authors.forename: Lilia
authors.initials: L
authors.lastname: Brinza
authors.forename: Julien
authors.initials: J
authors.lastname: Meunier
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Michallet
authors.forename: Aurélie
authors.initials: A
authors.lastname: Laugraud
authors.forename: Claudette
authors.initials: C
authors.lastname: Ah-Soon
authors.forename: Anne
authors.initials: A
authors.lastname: Wierinckx
authors.forename: Marc
authors.initials: M
authors.lastname: Castellazzi
authors.forename: Joël
authors.initials: J
authors.lastname: Lachuer
authors.forename: Christian
authors.initials: C
authors.lastname: Gautier
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marvel
authors.forename: Yann
authors.initials: Y
authors.lastname: Leverrier
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: D016329:Sp1 Transcription Factor