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Molecular and Cellular Biology, October 1998, p. 6063-6074, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

FGF-18, a Novel Member of the Fibroblast Growth Factor Family, Stimulates Hepatic and Intestinal Proliferation

Mickey C.-T. Hu,1,* Wan R. Qiu,1 You-ping Wang,1 Dave Hill,2 Brian D. Ring,2 Sheila Scully,2 Brad Bolon,2 Margaret DeRose,3 Roland Luethy,4 W. Scott Simonet,3 Tsutomu Arakawa,5 and Dimitry M. Danilenko2

Departments of Cell Biology,1 Pathology,2 Molecular Genetics,3 Computational Biology,4 and Protein Chemistry,5 Amgen, Inc., Thousand Oaks, California 91320

Received 13 March 1998/Returned for modification 27 April 1998/Accepted 1 July 1998

The fibroblast growth factors (FGFs) play key roles in controlling tissue growth, morphogenesis, and repair in animals. We have cloned a novel member of the FGF family, designated FGF-18, that is expressed primarily in the lungs and kidneys and at lower levels in the heart, testes, spleen, skeletal muscle, and brain. Sequence comparison indicates that FGF-18 is highly conserved between humans and mice and is most homologous to FGF-8 among the FGF family members. FGF-18 has a typical signal sequence and was glycosylated and secreted when it was transfected into 293-EBNA cells. Recombinant murine FGF-18 protein (rMuFGF-18) stimulated proliferation in the fibroblast cell line NIH 3T3 in vitro in a heparan sulfate-dependent manner. To examine its biological activity in vivo, rMuFGF-18 was injected into normal mice and ectopically overexpressed in transgenic mice by using a liver-specific promoter. Injection of rMuFGF-18 induced proliferation in a wide variety of tissues, including tissues of both epithelial and mesenchymal origin. The two tissues which appeared to be the primary targets of FGF-18 were the liver and small intestine, both of which exhibited histologic evidence of proliferation and showed significant gains in organ weight following 7 (sometimes 3) days of FGF-18 treatment. Transgenic mice that overexpressed FGF-18 in the liver also exhibited an increase in liver weight and hepatocellular proliferation. These results suggest that FGF-18 is a pleiotropic growth factor that stimulates proliferation in a number of tissues, most notably the liver and small intestine.

* Corresponding author. Mailing address: Amgen, Inc., 14-1-D, Thousand Oaks, CA 91320. Phone: (805) 447-6721. Fax: (805) 447-1982. E-mail: mhu{at}amgen.com.

Molecular and Cellular Biology, October 1998, p. 6063-6074, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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