Two distinct controls of mitotic cdk1/cyclin B1 activity requisite for cell growth prior to cell division.
Cell growth prior to cell division is restricted by the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complexes. Recently, we identified that the death-effector domain (DED) containing protein, DEDD, acts as a novel inhibitor of mitotic Cdk1/cyclin B1, influencing cell size. Like cyclin B1, DEDD protein levels specifically peak during the G(2)/M phase. In the nucleus, DEDD associates with Cdk1/cyclin B1 complexes, via direct binding to cyclin B1, and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD(-/-)) embryonic fibroblasts is increased compared to that in DEDD(+/+) cells. This accelerates mitotic progression in DEDD(-/-) cells, with a shortened G(2)/M phase, reduced rRNA, and diminished cell volume. Likewise, DEDD(-/-) mice show decreased body and organ weights relative to DEDD(+/+) mice. Interestingly, the DED domain is not involved in the association of DEDD with Cdk1/cyclin B1, but is indispensable for the cell sizing function of DEDD. Together, in addition to the well-established machinery for activation of Cdk1 through dephosphorylation of its inhibitory-residues, we propose a novel mechanism for impeditive regulation of mitotic Cdk1/cyclin B1 mediated by DEDD within the nucleus, which allows sufficient cell growth prior to cell division.
Miyazaki
Toru
T
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. tm@m.u-tokyo.ac.jp
Arai
Satoko
S
D000818:Animals; D049628:Body Size / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D049108:Cell Enlargement; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D008954:Models, Biological
C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D053418:Death Domain Receptor Signaling Adaptor Proteins; C486432:Dedd protein, mouse; D016203:CDC2 Protein Kinase