A novel mitochondrial protein DIP mediates E2F1-induced apoptosis independently of p53.
The transcription factor E2F1 does not only induce cell proliferation but also shows the strongest proapoptotic effect of all E2F family members as part of an antitumor safeguard mechanism. We have recently identified KIAA0767 as a novel p53-independent target of E2F1. Here, we investigated the biological function of interaction. Overexpression studies of KIAA0767, termed D(eath)-I(nducing)-P(rotein), revealed its strong proapoptotic effect. DIP greatly reduced cell viability in several in vitro systems accompanied by typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase. Endogenous DIP levels increased following E2F1 activation. Yet, inhibition of endogenous DIP function by small interfering RNA rescued p53-negative cells from E2F1-induced apoptosis, indicating that DIP is an essential mediator of the p53-independent E2F1 death pathway. Localization studies showed that DIP localizes to the mitochondria, where endogenous DIP is upregulated following E2F1 induction. These results provide new insights to the incompletely understood regulatory mechanisms of E2F1-induced apoptosis.
Stanelle
J
J
Department of Vectorology and Experimental Gene Therapy, Rostock University, Schillingallee 70, Rostock, Germany.
Tu-Rapp
H
H
Pützer
B M
BM
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C503369:GRAMD4 protein, human; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53