title: Mechanism of E2F1-induced apoptosis in primary vascular smooth muscle cells.
abstract: OBJECTIVE
  The transcription factor E2F1 serves as a major regulator of the cell-cycle by controlling G1-S phase transition. However, apart from its proliferative function high levels of deregulated E2F1 are capable of inducing apoptosis depending on the cellular context. In particular the tumor suppressor p53 and its homologue p73 are implicated in this proapoptotic function.
  
  
  METHODS
  Here, we investigated the mechanistic basis for E2F1-mediated apoptosis in vascular smooth muscle cells (VSMCs) which have previously been shown to be E2F1-responsive.
  
  
  RESULTS
  Interestingly, E2F1-expression in these cells induced clear signs of apoptosis in the absence of any proliferative activity. Although cell-cycle regulated genes such as CCNE1 and CDC25A were activated, BrdU-staining revealed no S-phase entry. Instead, a rapid loss of cell viability by induction of apoptosis was observed. Using a transactivation-defective E2F1-mutant, we show that apoptosis induction is independent of the transactivation function and therefore independent of ARF and p73. However, this mutant retains its ability to stabilize and phosphorylate p53, suggesting that p53 is sufficient for the effect of E2F1.
  
  
  CONCLUSIONS
  VSMCs therefore represent a cellular system in which the transactivation-independent, proapoptotic activity of E2F1 is the primary cellular function. Ectopic expression of E2F1 might therefore be a suitable therapy to prevent VSMC hyperproliferation.
authors.affiliation: Center for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Stanelle
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.forename: Florian
authors.initials: F
authors.lastname: Rödicker
authors.forename: Karin
authors.initials: K
authors.lastname: Köhler
authors.forename: Carmen
authors.initials: C
authors.lastname: Theseling
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005434:Flow Cytometry; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53