Cdc6 Protein Obstructs Apoptosome Assembly and Consequent Cell Death by Forming Stable Complexes with Activated Apaf-1 Molecules

• Published in: The Journal of biological chemistry 2012-05, Vol.287 (22), p.18573-18583
• Main Authors: Niimi, Shinichiro, Arakawa-Takeuchi, Shiho, Uranbileg, Baasanjav, Park, Jun-ha, Jinno, Shigeki, Okayama, Hiroto
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Anoikis; Apaf-1; Apoptosomes; Apoptotic Protease-Activating Factor 1 - metabolism; Caspase; Caspase 9 - metabolism; Cdc6; CDK (Cyclin-dependent Kinase); Cell Biology; Cell Cycle; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell Death; Cells, Cultured; E2F Transcription Factor; Enzyme Activation; Hydrolysis; Mice; mTORC1; Nuclear Proteins - metabolism; Nuclear Proteins - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.347690

Cdc6 is the bifunctional AAA+ ATPase that assembles prereplicative complexes on origins of replication and activates p21CIP1- or p27KIP1-bound Cdk2. During the G1-S transition, the Cdc6 gene essential for chromosomal replication is activated by the E2F transcriptional factor. Paradoxically, Apaf-1 encoding the central component of the apoptosome is also activated at the same time and by E2F. Consequently, genes for antipodal life and death are regulated in the same manner by the same transcriptional factor. Here we report a striking solution to this paradox. Besides performing prereplicative complex assembly and Cdk2 activation, Cdc6 obstructed apoptosome assembly by forming stable complexes very likely with a monomer of cytochrome c-activated Apaf-1 molecules. This function depended on its own ATPase domain but not on the cyclin-binding motif. In proliferating rodent fibroblasts, Cdc6 continued to block apoptosome assembly induced by a non-cytochrome c or some other mechanism, suppressing seemingly unintended apoptosis when promoting cell proliferation. Thus, Cdc6 is an AAA+ ATPase with three functions, all working for life. The apoptosome is a major apparatus for intrinsic stimulus-induced apoptosis. Cdc6, known to assemble prereplicative complexes on replication origins and activate p21CIP1-/p27KIP1-bound Cdk2, obstructs cytochrome c- or some other mechanism-induced apoptosome assembly by forming stable complexes with activated Apaf-1. Cdc6 is an AAA+ ATPase with three functions, all working for life. These results redefine the role of Cdc6 in cell proliferation.