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

Abstract

؊/؊ cells and tissues. Consequently, as in S6K1 ؊/؊ mice, the insulin mass within pancreatic islets was reduced in DEDD ؊/؊ mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.Cell size is closely related to specialized cell function and to the specific patterning of tissues in the body. Cell sizing is regulated mainly by two mechanisms: cell cycle control and the biochemical response to nutrients and/or growth factors (1-5). 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). Although the absence of DEDD did not apparently influence progression of apoptosis (10), we found that during mitosis, DEDD is associated with Cdk1-cyclin B1 and that it decreases the kinase activity of Cdk1. 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. This reaction increases the number of ribosomes and the efficacy of protein synthesis, thus critically promoting cell growth (16 -18). Therefore, mice deficient for S6K1 (S6K1 Ϫ/Ϫ ) had reduced cell and body size (19 -23). This effect also involves S6K1 in maintenance of glucose tolerance. S6K1 * This work was supported, in whole or in part, by National Institutes of Health Grant 5RO1AI50948-05. This work was also supported by grants-in-aid from the Ministry of Education, Sports, Culture, Science, and Technology, Japan, the Takeda Science Foundation (to T. M. and S. A.), the Mitsubishi Pharma Research Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Danone Institute of Nutrition for Health, the Uehara Memorial Fou...

Death effector domain–containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice

“…Furthermore, DEDD associated with cyclin D3. This is similar to our previous observations that DEDD binds to various proteins such as cyclin B1, S6K1, and Akt (8)(9)(10)(11). As shown in Figure 6B, immunoprecipitation in HEK293T cells expressing both FLAG-tagged cyclin D3 and hemagglutinin-tagged (HA-tagged) DEDD showed that the two proteins coprecipitated, indicating that DEDD may facilitate a complex with cyclin D3.…”

“…Consistently, depletion of DEDD results in a shortened mitotic duration, an overall decrease in the amount of cellular rRNA and protein, and decreased cell and body size (8,9). In addition to the function of DEDD as a cell-cycle regulator, we recently determined that DEDD associates with S6K1 (10) and Akt (11), major elements of the signaling cascade involving mitogen-related PI3K. Such associations support the roles of S6K1 activity and Akt protein stability, respectively, in contributing to the maintenance of glucose homeostasis in the body (10,11).…”

“…In addition to the function of DEDD as a cell-cycle regulator, we recently determined that DEDD associates with S6K1 (10) and Akt (11), major elements of the signaling cascade involving mitogen-related PI3K. Such associations support the roles of S6K1 activity and Akt protein stability, respectively, in contributing to the maintenance of glucose homeostasis in the body (10,11). Hence, DEDD is multifunctional and is involved in different physiological mechanisms.…”

Developmental regulation of decidual cell polyploidy at the site of implantation

“…DEDD is associated with CyclinB1/Cdk1 activity; specially decreasing the activity of Cdk1 allowing for sufficient ribosomal RNA/protein synthesis and cell growth prior to cell division by inhibiting Cdk1 regulated mitotic progression (39, 40). DEDD also interacts with Akt and S6K1 within the PI3K signaling cascade (41, 42). Dedd null mice are completely sterile, and the infertility is likely secondary to decidualization defects.…”

DEDD Interacts with PI3KC3 to Activate Autophagy and Attenuate Epithelial–Mesenchymal Transition in Human Breast Cancer

“…DEDD plays an important role in CD95-mediated apoptosis in response to the activation of TNF-a through activating caspase-3 in cytoplasm or caspase-6 in nucleus as a scaffold protein (14). Recent studies found that DEDD can suppress the activity of Cdk1/ cyclin B1 complexes and keep S6K1 activity, suggesting that DEDD participates in the regulation of cell cycle and inhibits cell mitosis (15)(16)(17). Although other members of DED-containing proteins such as FADD have been implicated in a diverse array of diseases such as Huntington's disease, Type II diabetes, autoimmune disease, arthritis, and cancer (18), there is no direct evidence to show whether DEDD involves in the regulation of tumor development, growth, invasion, and metastasis.…”