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

Kurabe, Nobuya; Arai, Satoko; Nishijima, Akemi; Kubota, Naoto; Suizu, Futoshi; Mori, Mayumi; Kurokawa, Jun; Kondo-Miyazaki, Miki; Ide, Tomohiro; Murakami, Kouji; Miyake, Katsuhisa; Ueki, Kohjiro; Koga, Hisashi; Yatomi, Yutaka; Tashiro, Fumio; Noguchi, Masayuki; Kadowaki, Takashi; Miyazaki, Toru

doi:10.1074/jbc.m808598200

Cited by 11 publications

(18 citation statements)

References 42 publications

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“…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.…”

Section: Decreased Akt Level In Dedd -/-Uteri and Increase In Polyplosupporting

confidence: 90%

“…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).…”

Section: Introductionmentioning

confidence: 66%

“…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.…”

Section: Introductionmentioning

confidence: 92%

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

Mori

Kitazume²,

Ose³

et al. 2011

J. Clin. Invest.

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During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking death effector domain-containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd -/-mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice. IntroductionApproximately 10%-15% of couples experience infertility during their reproductive years, owing mainly to implantation failure. Among the reasons underlying such failure, defective development of functional decidua at the implantation site within the uterus has recently been highlighted (1-3). In response to implantation, stromal cells immediately surrounding the mucosal crypt where the embryo is embedded proliferate extensively and undergo differentiation into polyploid decidual cells, forming an avascular primary decidual zone, followed by a broad, well-vascularized secondary decidual zone. It is believed that this decidual structure is important for the provision of nutrition to the developing embryo and also acts as a barrier against uncontrolled trophoblast proliferation until the placenta develops. Analyses of mutant mice that show female infertility, such as in knockout mice for homeobox A10 (Hoxa10) (4, 5) or IL-11 receptor (6), have contributed to the investigation of the molecular mechanisms involved in decidualization. Recent evidence has implicated cell-cycle regulation as being essential for both the proliferation and differentiation of stromal cells. In particular, Das and colleagues reported that cyclin D3-dependent activation of cyclin-dependent kinase 4 (Cdk4) or Cdk6 appears to be involved sequentially in those two events during decidua formation (7). In addition to these essential elements, in this report, we present data indicating that the death effector domaincontaining (DED-containing) protein DEDD is indispensable for the maturation of decidual cells and support of female fertility in mice.We previously found that the DEDD protein, initially described as...

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Section: Decreased Akt Level In Dedd -/-Uteri and Increase In Polyplosupporting

confidence: 90%

Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 92%

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

Mori

Kitazume²,

Ose³

et al. 2011

J. Clin. Invest.

Self Cite

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“…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.…”

Section: Mechanisms Of Polyploidizationmentioning

confidence: 99%

Developmental regulation of decidual cell polyploidy at the site of implantation

Sroga

Ma²,

Das³

2012

Front Biosci

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Polyploidy has been reported in several animal cells, as well as within humans; however the mechanism of developmental regulation of this process remains poorly understood. Polyploidy occurs in normal biologic processes as well as in pathologic states. Decidual polyploid cells are terminally differentiated cells with a critical role in continued uterine development during embryo implantation and growth. Here we review the mechanisms involved in polyploidy cell formation in normal developmental processes, with focus on known regulatory aspects in decidual cells.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Epithelial-to-mesenchymal transition (EMT), a crucial developmental program, contributes to cancer invasion and metastasis. In this study, we show that death-effector domain-containing DNA-binding protein (DEDD) attenuates EMT and acts as an endogenous suppressor of tumor growth and metastasis. We found that expression levels of DEDD were conversely correlated with poor prognosis in patients with breast and colon cancer. Both in vitro and in vivo, overexpression of DEDD attenuated the invasive phenotype of highly metastatic cells, whereas silencing of DEDD promoted the invasion of nonmetastatic cells. Via direct interaction with the class III PI-3-kinase (PI3KC3)/Beclin1, DEDD activated autophagy and induced the degradation of Snail and Twist, two master regulators of EMT. The DEDD-PI3KC3 interaction led to stabilization of PI3KC3, which further contributed to autophagy and the degradation of Snail and Twist. Together, our findings highlight a novel mechanism in which the intracellular signaling protein DEDD functions as an endogenous tumor suppressor. DEDD expression therefore may represent a prognostic marker and potential therapeutic target for the prevention and treatment of cancer metastasis. Cancer Res; 72(13); 3238-50. Ó2012 AACR.

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

Cited by 11 publications

References 42 publications

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

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

Developmental regulation of decidual cell polyploidy at the site of implantation

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

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