Death-effector domain-containing protein DEDD is an inhibitor of mitotic Cdk1/cyclin B1

Abstract

Accumulating evidence has shown that many molecules, including some cyclin-dependent kinases (Cdks) and cyclins, as well as the death-effector domain (DED)-containing FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which also possesses the DED domain, acts as a novel inhibitor of the mitotic Cdk1/cyclin B1 complex. DEDD associates with mitotic 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 with that in DEDD ؉/؉ cells, which results in accelerated mitotic progression, thus exhibiting a shortened G2/M stage. Interestingly, DEDD ؊/؊ cells also demonstrated decreased G1 duration, which perhaps enhanced the overall reduction in rRNA amounts and cell volume, primarily caused by the rapid termination of rRNA synthesis before cell division. Likewise, DEDD ؊/؊ mice show decreased body and organ weights relative to DEDD ؉/؉ mice. Thus, DEDD is an impeder of cell mitosis, and its absence critically influences cell and body size via modulation of rRNA synthesis.apoptosis ͉ cell cycle ͉ cell size ͉ cyclin-dependent kinase ͉ mitosis C ell size control is tightly associated with cell cycle regulation.The consensus is that cells predominantly increase their volume during the G 1 cell cycle phase (1-3). However, evidence has demonstrated that a proper cell growth also undergoes before cell division (4, 5), where rRNA and protein synthesis achieve maximal activity. The duration of this period is defined by the activation of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complexes, which is proceeded through dephosphorylation of the inhibitory residues of Cdk1 and Tyr-15, and also Thr-14 in higher eukaryotes, by the Cdc25 phosphatase family (4-10), followed by translocation of Cdk1/cyclin B1 into the nucleus. Thus, defects in Cdc25 genes delay mitotic entry, resulting in increased cell size (11-13). In contrast, an inadequate duration before division, due to aberrant phosphorylation of Tyr-15, causes cells to enter mitosis before sufficient growth, resulting in decreased size of the daughter cells (14-17). Interestingly, the loss of Wee1-related kinases, responsible for phosphorylation of Thr-14/Tyr-15, causes premature cell division in yeast, Xenopus, or Drosophila cells, but not in higher mammalian cells (4,5,9,10,(15)(16)(17)(18). This suggests the presence of alternative mechanism(s), which may also influence cell size, particularly in mammalian cells. However, the responsible mechanisms have remained unclear.Linkage of cell cycle and apoptosis has been recognized for many molecules, including some Cdks and cyclins (19,20). Recently, it was also demonstrated that the death-effector domain (DED)-containing molecule FADD regulates mitosis (21). The DED domain of Ϸ80 amino acid residues is well conserved in various death-inducing proteins (22-24). The DED of FADD recruits two DED-containing caspases, caspase-8 and caspase-10, to form the deat...

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

“…Although the cell division cycle and apoptosis might appear to be quite different from a physiological perspective, recent evidence suggests that they are intertwined, and that an enzyme in one system might also have an important role in the other system. [21,22] The degree of apoptosis in our study is relatively lower than previously reported with annexin V staining [15,23,24]. Similar were the findings of our previous study in a smaller group of patients [14].…”

The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation

“…Schumann et al (39) reported that the Fas pathway, where many DED-containing elements are associated, is involved in ␤ cell secretory function. Thus, DED-containing proteins might also influence metabolic homeostasis through apoptosis cascades, although DEDD Ϫ/Ϫ cells or mice showed no apparent defect in apoptosis (10,11). Future analyses will clarify this issue more precisely.…”

“…This response impedes the Cdk1-dependent mitotic program to shut off synthesis of ribosomal RNA (rRNA) and protein and is consequently useful in gaining sufficient cell growth prior to cell division. Depletion of DEDD consistently results in a shortened mitotic duration and an overall reduction in the amount of cellular rRNA and protein and, furthermore, in cell and body size (10,11).…”

“…This response impedes the Cdk1-dependent mitotic program to shut off synthesis of ribosomal RNA (rRNA) and protein and is consequently useful in gaining sufficient cell growth prior to cell division. Depletion of DEDD consistently results in a shortened mitotic duration and an overall reduction in the amount of cellular rRNA and protein and, furthermore, in cell and body size (10,11).Of the biochemical responses responsible for cell sizing, the signaling cascade involving phosphatydilinositol 3-kinase (PI3K) and its downstream target of rapamycin (TOR) is most crucial (13)(14)(15). In mammals, upon stimulation by growth factors, including insulin, the mammalian TOR (mTOR) cooperates with PI3K-dependent effectors to activate S6K1, thereby phosphorylating the 40 S ribosomal protein S6, and subsequently enhances translation of the 5Ј-terminal oligopyrimidine sequences that encode components of the translational machinery.…”

“…During cell cycle progression, both the G 1 (which is believed to be dominant) and the G 2 periods are important for cells to increase their volume (6 -9). In addition, we recently provided evidence that the mitotic period (M phase) also influences cell size, through analysis of DEDD-deficient mice (10,11). The DEDD molecule was initially described as a member of the death effector domain (DED) 2 -containing protein family (12).…”