DEDD negatively regulates transforming growth factor‐β1 signaling by interacting with Smad3

Jishan, Xue; Hua, Fang; Lv, Qi; Lin, Heng; Wang, Zi Yan; Yan, Jun; Liu, Jin Wen; Lv, Xiao Xi; Yang, Hong Zhen; Hu, Zhuo Wei

doi:10.1016/j.febslet.2010.05.043

Cited by 6 publications

(11 citation statements)

References 15 publications

(26 reference statements)

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“…Interestingly, a very recent study by Mori and colleagues report that DEDD deficiency results in a defect in uterine decidualization and infertile because of reducing Akt expression, indicating that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice (43). This finding is consistent and support to the fact that DEDD is involved in the regulation of embryos developmental programs including EMT (19). However, it needs to point out, previous work indicated that DEDD can enter nucleus to inhibit rDNA transcription (25), regulate cell cycle, and inhibit cell mitosis to reduce cell and body size via modulation of rRNA synthesis (17), attenuate protein synthesis, and promote apoptosis (44,45).…”

Section: Discussionsupporting

confidence: 79%

“…Thus, alterations in the expression of PI3KC3 result in either activation or inactivation of autophagy-dependent degradation of Snail/ Twist and other positive EMT markers. Despite we do not know the precise mechanism how DEDD interacts with PI3KC3 to maintain the stability of this protein and why loss of DEDD expression promotes the degradation of PI3KC3, recent work indicate that DEDD induces a diversity of cell biologic activity through interacting with several key molecules to attenuate or support the stability of these proteins in the cells (19,46). Thus, a key question to be addressed is: what program is responsible for shutdown or turn-on of DEDD expression under the physiologic or pathologic situations.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent work indicates that DEDD attenuates TGF-b1/ Smad3 signaling through interacting with transcription factor Smad3 to suppress the TGF-b1/Smad3-mediaed invasion in cancer cells (19). In this study, we have showed that the expression level of DEDD in breast and colon cancers correlates conversely with the poor prognosis of breast and colon cancers: the lower is DEDD expression in beast and colon cancers, the higher is the cancer-induced death rate because the expression level of DEDD decides the metastatic phenotypes of the cancer cells, including migration, invasion, growth, and metastasis (1, 5).…”

Section: Discussionmentioning

confidence: 99%

“…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. Using a yeast 2-hybrid screening system, we have recently identified a number of molecules, including DEDD and TRB3, physically interacting with TGF-b1 signal molecule SMAD3 to attenuate or enhance TGF-b1/Smad3-mediated cancer cell invasion or EMT (19,20).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…FOXM1 is also frequently aberrantly activated in many human cancers, including breast cancer (17,32). Specific and diverse TGF-β functions depend on the SMADs as a central node for the integration of TGF-β signaling with other signaling pathways (1,33). In the present study, we found that FOXM1 specifically interacts with SMAD3, which supports the recent observations that SMAD3, but not SMAD2, is required for TGF-β-induced metastasis in breast cancer (34).…”

Section: Tablesupporting

confidence: 80%

Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β–dependent cancer metastasis

Xue¹,

Lin²,

Chiu³

et al. 2014

J. Clin. Invest.

154

145

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A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.

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Use of the Tumor Repressor DEDD as a Prognostic Marker of Cancer Metastasis

Hua

2014

Methods in Molecular Biology

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DEDD, a member of a family of death effector domain-containing proteins, plays crucial roles in mediating apoptosis, regulating cell cycle, and inhibiting cell mitosis. Our recent work demonstrates that DEDD is a novel tumor repressor, which impedes metastasis by reversing the epithelial-mesenchymal transition (EMT) process in breast and colon cancers. DEDD expression therefore may represent a prognostic marker and potential therapeutic target for the prevention and treatment of cancer metastasis. To reveal the anti-metastatic roles of DEDD in these cancer cells, a number of experiments, including immunohistochemistry, the establishment of stably overexpressing or silencing cancer cells, chemoinvasion assay, soft agar assay, protein degradation, and protein-protein interaction were used in our in vitro and in vivo studies. This chapter focuses on the details of these experiments to provide references for the researchers to investigate the function of a gene in the regulation of tumor metastasis.

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DEDD negatively regulates transforming growth factor‐β1 signaling by interacting with Smad3

Cited by 6 publications

References 15 publications

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

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

Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β–dependent cancer metastasis

Use of the Tumor Repressor DEDD as a Prognostic Marker of Cancer Metastasis

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