WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: Augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates

Katoh, Masuko; Katoh, Masaru

doi:10.3892/ijmm.19.1.197

Cited by 25 publications

(25 citation statements)

References 34 publications

(40 reference statements)

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“…2). Interestingly, endothelial cell-specific Dkk-2 Tg mice display a vascular phenotype similar to Jag-1 Tg mice (74), and Jag-1 promotes Dkk-2 expression through Notch in human small intestine stem cells (75). These results imply that Dkk-2 might regulate angiogenic activity of endothelial cells through crosstalk with Notch signaling.…”

Section: Dickkopf-2mentioning

confidence: 85%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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SummaryThe Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists.

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Section: Dickkopf-2mentioning

confidence: 85%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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“…Recent in silico analysis suggested that DKK2 is a Notch signaling target in intestinal stem cells (33). However, Notch-response elements were detected in the promoter region of DKK2 of human, chimpanzee, and rat, but not in cow and mouse (33). Thus, it remains unclear whether angiogenic action of DKK2 is functionally correlated with Notch signaling.…”

Section: Figurementioning

confidence: 95%

“…Thus, the expression pattern and Tg phenotypes point to a potential relationship between Jag1 and DKK2 in sprouting angiogenesis. Recent in silico analysis suggested that DKK2 is a Notch signaling target in intestinal stem cells (33). However, Notch-response elements were detected in the promoter region of DKK2 of human, chimpanzee, and rat, but not in cow and mouse (33).…”

Section: Figurementioning

confidence: 99%

The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells

Kim¹,

Park²,

Choi³

et al. 2011

J. Clin. Invest.

103

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Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report that Dickkopf1 (DKK1) and Dickkopf2 (DKK2), originally known as WNT antagonists, play opposite functional roles in regulating angiogenesis. DKK2 induced during EC morphogenesis promoted angiogenesis in cultured human endothelial cells and in in vivo assays using mice. Its structural homolog, DKK1, suppressed angiogenesis and was repressed upon induction of morphogenesis. Importantly, local injection of DKK2 protein significantly improved tissue repair, with enhanced neovascularization in animal models of both hind limb ischemia and myocardial infarction. We further showed that DKK2 stimulated filopodial dynamics and angiogenic sprouting of ECs via a signaling cascade involving LRP6-mediated APC/Asef2/Cdc42 activation. Thus, our findings demonstrate the distinct functions of DKK1 and DKK2 in controlling angiogenesis and suggest that DKK2 may be a viable therapeutic target in the treatment of ischemic vascular diseases.

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“…Exonintron boundaries were determined based on the consensus sequence of exon-intron junctions ('gt ..... ag' rule of intronic sequence) and codon usage within the coding region. Conserved transcription factor-binding sites within promoter regions were then searched for based on the Match program, Genetyx program, and manual curation as previously described (43)(44)(45) In silico expression analyses. Expressed sequence tags (ESTs) derived from human HES/HEY family members were searched for using the BLAST programs as previously described (48)(49)(50) …”

Section: Methodsmentioning

confidence: 99%

Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer

Katoh¹,

Katoh²

2007

Int J Oncol

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Abstract. Notch signaling pathway maintains stem cells through transcriptional activation of HES/HEY family members to repress tissue-specific transcription factors. Here, comparative integromic analyses on HES/HEY family members were carried out. HES3 gene encodes two isoforms due to alternative promoters. Complete coding sequence of HES3 variant 2 was determined by curating CX755241.1 EST. Refined phylogenetic analysis using HES3 variant 2 instead of variant 1 revealed that mammalian bHLH transcription factors with Orange domain were grouped into HES subfamily (HES1, HES2, HES3, HES4, HES5, HES6, HES7) and HEY subfamily (HEY1, HEY2, HEYL, HESL/HELT, DEC1/ BHLHB2, DEC2/BHLHB3). Eight amino-acid residues were added to the C-terminal WRPW motif in human HES3 due to lineage specific T to G nucleotide change at stop codon of chimpanzee, rat, and mouse HES3 orthologs. HES1 and HES3 were expressed in undifferentiated embryonic stem (ES) cells. HES1 was also expressed in fetal tissues, and regenerating liver. HES1, HEY1 and HEY2 were expressed in endothelial cells. HES1, HES4 and HES6 were expressed in gastric cancer, HES1 and DEC1 in pancreatic cancer, HES1, HES2, HES4, HES6 and DEC2 in colorectal cancer. HES6 was also expressed in other tumors, such as brain tumors, melanoma, small cell lung cancer, retinoblastoma, ovarian cancer, and breast cancer. Double NANOG-binding sites, CSL/ RBPSUH-binding site and TATA-box in HES1 promoter, NANOG-, SOX2-, POU5F1/OCT3/OCT4-binding sites and TATA-box in HES3 promoter, double CSL-binding sites in HES5 promoter, SOX2-, POU-binding sites and TATA-box in HES6 promoter, and CSL-binding site in HEY1, HEY2 and HEYL promoters were evolutionarily conserved. However, double CSL-binding sites in mouse Hes7 promoter were not conserved in human HES7 promoter. Together these facts indicate that HES1 and HES3 were target genes of the ES cellspecific network of transcription factors, and that HES1, HES5, HEY1, HEY2 and HEYL were target genes of Notch signaling pathway.

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WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: Augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates

Cited by 25 publications

References 34 publications

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells

Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer

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