title: Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F.
abstract: We have isolated several peptides from random peptide phage display libraries that specifically recognize the cell cycle regulatory transcription factor E2F and inhibit DNA binding of E2F/DP heterodimers (E2F-1, E2F-2, E2F-3, E2F-4 or E2F-5, and DP-1). The inhibitory efficiency could be strongly enhanced by generating branched tetravalent molecules. To analyse the biological consequences of peptide-mediated E2F inhibition, we fused two of these branched molecules to a cell-penetrating peptide derived from the HTV-Tat protein. Incubation of human tumor cells with these branched Tat-containing peptides led to an inhibition of cell proliferation and induction of apoptosis. These results provide new insights into the function of E2F and further validate E2F as a potential therapeutic target in proliferative diseases.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Emil-Mannkopff-Strasse 2, D-35033 Marburg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Montigiani
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D006367:HeLa Cells; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D050699:E2F3 Transcription Factor; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D050700:E2F5 Transcription Factor; D019151:Peptide Library; D010455:Peptides; D014157:Transcription Factors; D004247:DNA