FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development.
beta-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize beta-catenin result in augmented gene transcription and play a major role in many human cancers. We employed microarrays to identify transcriptional targets of deregulated beta-catenin in a human epithelial cell line (293) engineered to produce mutant beta-catenin and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/beta-catenin pathway. Two genes strongly induced in both systems-FGF20 and DKK1-were studied in detail. Elevated levels of FGF20 RNA were also observed in adenomas from mice carrying the Apc(Min)allele. Both XFGF20 and Xdkk-1 are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. Furthermore, FGF20 and DKK1 appear to be direct targets for beta-catenin/TCF transcriptional regulation via LEF/TCF-binding sites. Finally, by using small inhibitory RNAs specific for FGF20, we show that continued expression of FGF20 is necessary for maintenance of the anchorage-independent growth state in RK3E cells transformed by beta-catenin, implying that FGF-20 may be a critical element in oncogenesis induced by the Wnt signaling pathway.
Chamorro
Mario N
MN
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Varmus Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Schwartz
Donald R
DR
Vonica
Alin
A
Brivanlou
Ali H
AH
Cho
Kathleen R
KR
Varmus
Harold E
HE
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; C501127:Dkk1 protein, mouse; C416003:FGF20 protein, human; C498812:Fgf20 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; C110182:dkk1 protein, Xenopus; D005346:Fibroblast Growth Factors