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Science 309 (5738): 1256-1259

Copyright © 2005 by the American Association for the Advancement of Science

Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium

Kyung-Ah Kim,1* Makoto Kakitani,2 Jingsong Zhao,1 Takeshi Oshima,2 Tom Tang,1 Minke Binnerts,1 Yi Liu,1 Bryan Boyle,1 Emily Park,1 Peter Emtage,1 Walter D. Funk,1{dagger} Kazuma Tomizuka2*{dagger}

Abstract: Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection into mice, the protein induced rapid onset of crypt cell proliferation involving ß-catenin stabilization, possibly by a process that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced intestinal mucositis and may have therapeutic application in gastrointestinal diseases.

1 Nuvelo, Inc., 675 Almanor Avenue, Sunnyvale, CA 94085, USA.
2 Pharmaceutical Research Laboratories, Pharmaceutical Division, Kirin Brewery Co., Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: wfunk{at}nuvelo.com (W.D.F.); ktomizuka{at}kirin.co.jp (K.T.)


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