Loss of Rb-E2F repression results in caspase-8-mediated apoptosis through inactivation of focal adhesion kinase.
Molecular hardwiring of the cell cycle to the apoptotic machinery is a critical tumor suppressor mechanism for eliminating hyperproliferative cells. Deregulation of the Rb-E2F repressor complex by genetic deletion or functional inhibition of Rb triggers apoptosis through both the intrinsic (caspase-9 mediated) and extrinsic (caspase-8 mediated) death pathways. Induction of the intrinsic pathway has been studied extensively and involves release of free E2F and direct transcriptional activation of E2F-responsive apoptotic genes such as ARF, APAF1, and CASP9. In contrast, the mechanisms leading to activation of the extrinsic pathway are less well understood. There is growing evidence that Rb-E2F perturbation induces the extrinsic pathway, at least in part, through derepression (as opposed to transactivation) of apoptotic genes. Here, we explore this possibility using cells in which Rb-E2F complexes are displaced from promoters without stimulating E2F transactivation. This derepression of Rb-E2F-regulated genes leads to apoptosis through inactivation of focal adhesion kinase and activation of caspase-8. These findings reveal a new mechanistic link between Rb-E2F and the extrinsic (caspase 8-mediated) apoptotic pathway.
Lieman
Jonathan H
JH
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, Missouri 63110, USA.
Worley
Lori A
LA
Harbour
J William
JW
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
C506592:APAF1 protein, human; C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496052:Ptk2 protein, rat; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020727:ADP-Ribosylation Factors