Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F.
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.
Montigiani
Silvia
S
Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Emil-Mannkopff-Strasse 2, D-35033 Marburg, Germany.
Müller
Rolf
R
Kontermann
Roland E
RE
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*
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