Dkk3 is required for TGF-β signaling during Xenopus mesoderm induction

Pinho, Sónia; Niehrs, Christof

doi:10.1111/j.1432-0436.2007.00185.x

Cited by 38 publications

(39 citation statements)

References 74 publications

(92 reference statements)

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“…A recent report suggested that REIC/Dkk-3 was essential for transforming growth factor-h (TGF-h) signaling during Xenopus mesoderm induction (23). However, no study directly showed the involvement of REIC/Dkk-3 in the TGF-h signaling pathway in mammalian cells.…”

Section: Discussionmentioning

confidence: 98%

Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

Kashiwakura

Ochiai

Watanabe³

et al. 2008

Cancer Research

118

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REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH 2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional downregulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed downregulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

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Section: Discussionmentioning

confidence: 98%

Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3–Induced Apoptosis

Kashiwakura

Ochiai

Watanabe³

et al. 2008

Cancer Research

118

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“…32 A crosstalk of Dkk-3 with TGF-beta signaling was recently shown during mesoderm induction in xenopus. 33 Thus, Dkk-3 might support TGF-b signaling, stromal reactivation and angiogenic remodeling processes in tumors. 11 In summary, our studies show a significant upregulation of Dkk-3 expression in tumor blood vessels as compared to vessels from healthy tissues.…”

Section: Discussionmentioning

confidence: 99%

The Dickkopf‐homolog 3 is expressed in tumor endothelial cells and supports capillary formation

Untergasser

Steurer

Zimmermann

et al. 2008

Intl Journal of Cancer

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A critical event in tumor growth and progression is the upregulation of angiogenesis. Thus, targeting angiogenesis has become an attractive treatment modality in cancer medicine. Our study analyzed various solid tumor types for the expression of Dkk-3, a cystein-rich, N-glycosylated secreted member of the dickkopf protein family that has been proposed as a tumor suppressor gene. Tissue microarrays of gliomas (n 5 30), high-grade non-Hodgkin's lymphomas (NHL, n 5 80), colorectal cancer (n 5 35) and melanoma (n 5 30) were immunohistochemically analyzed for Dkk-3 and CD31 expression. Moreover, the effects of Dkk-3 were studied in vitro in primary endothelial colony-forming cells (ECFC) and in vivo in a mouse melanoma model. In comparison to normal tissue, the number of blood vessels expressing Dkk-3 was increased in glioma, high-grade NHL, melanoma and colorectal carcinoma. Confocal laser scanning microscopy revealed that Dkk-3 vesicles localized also in Weibel Palade bodies. In vitro cell proliferation and migration of ECFC was not significantly affected by adenoviral overexpression or siRNA-mediated downregulation of Dkk-3. Interestingly, tube formation in matrigel decreased after downregulation of Dkk-3 and increased after adenoviral overexpression. Stable overexpression of murine Dkk-3 in B16F10 cells significantly increased microvessel density in the C57/BL6 melanoma model. Thus, we postulate a novel function of Dkk-3 in endothelial cells as a differentiation factor involved in remodeling the tumor vasculature. ' 2007 Wiley-Liss, Inc.Key words: angiogenesis; glioma; lymphoma; melanoma; colorectal cancer; Dickkopf-3 Growth, progression and metastasis of solid tumors are strongly dependent on the supply of oxygen and nutrients. 1 Without adequate blood supply tumors become hypoxic, acidotic and necrotic. Therefore, growing tumors induce an angiogenic switch 2 and produce a variety of growth factors that are responsible either for remodeling of the pre-existing vascular network by means of angiogenic sprouting or intus-susceptive growth or for neovascularization by recruiting circulating endothelial cells. 3 Capillaries of the tumor vascular bed show a variety of structural abnormalities, such as the lack of a basement membrane, low numbers of surrounding pericytes, mosaic vessel structure and altered expression patterns of leukocyte adhesion molecules. 4 On the molecular level, tumor endothelial cells show a distinct gene expression profile 5 that differs from that of normal endothelial cells. 6 Thus, markers specifically expressed or overexpressed on tumor endothelial cells or secreted into the perivascular space are potential candidates for vascular targeting. 7 Among the dickkopf family of secreted modulators of wnt signalling, Dkk-3 is the most divergent member with still unknown signal transduction and function. 8 Dkk-1 and Dkk-2 have been shown to bind to Kremen receptors, resulting in down-regulation of the Wnt-coreceptor lipoprotein-related protein from the cell surface. 9-11 Dkk-1 knock-out mice show se...

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“…As for Dkk1 and Dkk2, a functional interaction with LRP6 has been shown for Dkk4. In contrast, Dkk3 does not bind LRP6 and does not affect Wnt signaling (Mao et al 2001;Mao and Niehrs 2003), but rather regulates transforming growth factor-b (TGF-b) signaling (Pinho and Niehrs 2007). Within LRP6, the last two YWTD -epidermal growth factor (EGF) repeat domains mediate binding to Dkk1 (Mao et al 2001).…”

Section: Mechanism Of Actionmentioning

confidence: 99%