Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium

Kim, Kyung-Ah; Kakitani, Makoto; Zhao, Jingsong; Oshima, Takeshi; Tang, Tom; Binnerts, M.E.; Liu, Yi; Boyle, Bryan; Park, Emily; Emtage, Peter; Funk, Walter D.; Tomizuka, Kazuma

doi:10.1126/science.1112521

Cited by 513 publications

(505 citation statements)

References 18 publications

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“…RSPO1 is a small secreted factor that is able to stimulate the canonical Wnt/β-catenin signaling pathway by increasing the levels of a Wnt co-receptor, LRP6 (low density lipoprotein receptorrelated protein 6) at the membrane of the cell (Binnerts et al, 2007, Kazanskaya et al, 2004, Kim et al, 2005, Kim et al, 2006a, Nam et al, 2006. Importantly, the Wnt/β-catenin pathway is active in the early developing ovary and inactive in the early developing testis (Chassot et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/β-catenin signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCFdependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-catenin; surprisingly four SRY sex reversed mutants with defective DNA binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of β-catenin involves neither DNA binding nor transactivation functions of SRY. β-catenin and SRY interact in-vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

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Section: Introductionmentioning

confidence: 99%

Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…It has been reported that RSPO2 and RSPO3 insertional activation is observed in the mouse mammary tumor virus model system (11,12). Administration of RSPO1 protein to mice induces rapid crypt cell proliferation, which causes a marked increase in the size of the small intestine (13). Seshagiri et al (14) identified that RSPO2 and RSPO3 transcript fusion occurs in 10% of colon tumors.…”

Section: Introductionmentioning

confidence: 99%

R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma

Yin

Wang

et al. 2017

Oncology Letters

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Abstract. Hepatocellular carcinoma (HCC) is a leading cause of malignant disease-associated mortality, particularly in China. The RSPO2 (R-spondin 2) gene is evolutionarily conserved in vertebrates and is involved in developmental and physiological processes. Importantly, RSPO2 has been reported to be associated with colon cancer and potentiate the Wnt/β-catenin signaling pathway. In the present study, enhanced expression of RSPO2 in HCC was observed using tissue microarray. Similarly, the expression level of RSPO2 was higher in HepG2, Huh7 and Hep3B cells but lower in Bel7404 and QGY7703 cells compared with human normal QSG7701 liver cells. Subsequently, gain-of-function studies indicated that RSPO2 promotes the proliferation and migration of QGY7703 cells based on lentivirus-based gene delivery. Furthermore, it was revealed that p21 and leptin, rather than vascular endothelial growth factor-A, are involved in the function of RSPO2 in QGY7703 cells. Particularly, the signal transducer and activator of transcription 3 (STAT3) and Wnt/β-catenin signaling pathways are involved in this process. Overexpression of RSPO2 resulted in the elevated expression of phosphorylated STAT3, β-catenin and c-Myc. Therefore, the present study is beneficial to the understanding of RSPO2-involved liver cancer transformation and drug discovery.

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“…Further studies are needed to define the molecular mechanisms involved in intestinal cell viability and injury repair, including studies of the WNT signaling pathway and R-spondin-1 [52], promitotic factors which may interact with glutamine to hasten intestinal recovery. Additionally, the interaction with other critical guttrophic nutrients such as zinc and arginine are critical targets for developing more efficient strategies to alleviate malabsorption and diarrhea due to undesirable intestinal mucositis, and to rebuild the small intestinal barrier, work which is currently underway in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Alanyl-Glutamine and Glutamine Supplementation Improves 5-Fluorouracil-Induced Intestinal Epithelium Damage In Vitro

et al. 2008

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In this study, we have examined the role of glutamine derivatives in reducing 5-fluorouracil (5-FU)-induced epithelial damage in an undifferentiated crypt intestinal cell line, IEC-6. In this model, we have investigated proliferation indirectly by detecting the enzyme-derived formazan dye from the tetrazolium salt WST-1 in viable cells at 24 and 48 h after 5-FU treatment. Migration was measured at 12 and 24 h after razor scraping of the cell monolayer. Cell death was measured by quantifying the percentage of apoptotic and necrotic figures by flow cytometry at 12 and 24 h following 5-FU challenge. Neither glutamine nor alanyl-glutamine prevented 5-FU-induced apoptosis and necrosis in IEC-6 cells at 12 and 24 h after 5-FU challenge. However, glutamine and alanyl-glutamine enhanced migration and proliferation when compared with 5-FU-treated controls (P <0.05). These new findings support our earlier study on the benefit of oral glutamine in enhancing epithelial recovery after 5-FU challenge.

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Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium

Cited by 513 publications

References 18 publications

Human SRY inhibits β-catenin-mediated transcription

Human SRY inhibits β-catenin-mediated transcription

R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma

Alanyl-Glutamine and Glutamine Supplementation Improves 5-Fluorouracil-Induced Intestinal Epithelium Damage In Vitro

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