Transcriptional regulation of AKT activation by E2F.
The pRB-E2F pathway is a downstream target of mitogenic signaling pathways. The E2F family of transcription factors has a pivotal role in regulating cell proliferation since it controls the timely expression of many genes that are required for cell cycle progression. Moreover, at least one member of this family, E2F1, can mediate apoptotic cell death. We show here that E2F also modulates the activity of a major signal transduction pathway: we demonstrate that E2F upregulates AKT activity through a transcription-dependent mechanism. We identify the adaptor protein Grb2 associated binder 2 (Gab2) as a direct E2F target gene and an essential effector of E2F-dependent AKT activation. AKT activation was shown to inhibit E2F1induced apoptosis. Therefore, our results suggest the existence of a negative feedback loop involving E2F and AKT.
Chaussepied
Marie
M
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Ginsberg
Doron
D
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004396:Coloring Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D008156:Luciferases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D001973:Bromodeoxyuridine